Discovery of the Clinical Candidate YY2201 as a Highly Potent and Selective ATR Inhibitor
ATR is one of the key DNA damage response (DDR) regulatory factors to maintain genome stability. ATR inhibition induces DNA damage accumulation and apoptosis in DDR kinase mutation or deficiency cancer cells through synthetic lethality, making it a promising target for treatment of cancers with DDR...
Saved in:
| Published in | Journal of medicinal chemistry Vol. 68; no. 5; pp. 5292 - 5311 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
WASHINGTON
American Chemical Society
13.03.2025
Amer Chemical Soc |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0022-2623 1520-4804 1520-4804 |
| DOI | 10.1021/acs.jmedchem.4c02380 |
Cover
Loading…
| Abstract | ATR is one of the key DNA damage response (DDR) regulatory factors to maintain genome stability. ATR inhibition induces DNA damage accumulation and apoptosis in DDR kinase mutation or deficiency cancer cells through synthetic lethality, making it a promising target for treatment of cancers with DDR defects. Herein, we describe the discovery and preclinical evaluation of YY2201, a highly potent and selective novel ATR inhibitor, with favorable ADME, safety pharmacology, and pharmacokinetics profiles. YY2201 efficiently inhibits tumor progression in broad-spectrum cancer types, both in vitro and in vivo. YY2201 shows superior in vivo anticancer efficacy and a better therapeutic index compared to AZD6738 in a lung cancer xenograft model. YY2201 also exhibits potent cancer suppression effects in combination with chemotherapy in vivo. Currently, the investigational new drug application of YY2201 has been approved by the FDA for further clinical investigation. |
|---|---|
| AbstractList | ATR is one of the key DNA damage response (DDR) regulatory factors to maintain genome stability. ATR inhibition induces DNA damage accumulation and apoptosis in DDR kinase mutation or deficiency cancer cells through synthetic lethality, making it a promising target for treatment of cancers with DDR defects. Herein, we describe the discovery and preclinical evaluation of YY2201, a highly potent and selective novel ATR inhibitor, with favorable ADME, safety pharmacology, and pharmacokinetics profiles. YY2201 efficiently inhibits tumor progression in broad-spectrum cancer types, both in vitro and in vivo. YY2201 shows superior in vivo anticancer efficacy and a better therapeutic index compared to AZD6738 in a lung cancer xenograft model. YY2201 also exhibits potent cancer suppression effects in combination with chemotherapy in vivo. Currently, the investigational new drug application of YY2201 has been approved by the FDA for further clinical investigation. ATR is one of the key DNA damage response (DDR) regulatory factors to maintain genome stability. ATR inhibition induces DNA damage accumulation and apoptosis in DDR kinase mutation or deficiency cancer cells through synthetic lethality, making it a promising target for treatment of cancers with DDR defects. Herein, we describe the discovery and preclinical evaluation of , a highly potent and selective novel ATR inhibitor, with favorable ADME, safety pharmacology, and pharmacokinetics profiles. efficiently inhibits tumor progression in broad-spectrum cancer types, both and . shows superior anticancer efficacy and a better therapeutic index compared to AZD6738 in a lung cancer xenograft model. also exhibits potent cancer suppression effects in combination with chemotherapy . Currently, the investigational new drug application of has been approved by the FDA for further clinical investigation. ATR is one of the key DNA damage response (DDR) regulatory factors to maintain genome stability. ATR inhibition induces DNA damage accumulation and apoptosis in DDR kinase mutation or deficiency cancer cells through synthetic lethality, making it a promising target for treatment of cancers with DDR defects. Herein, we describe the discovery and preclinical evaluation of YY2201, a highly potent and selective novel ATR inhibitor, with favorable ADME, safety pharmacology, and pharmacokinetics profiles. YY2201 efficiently inhibits tumor progression in broad-spectrum cancer types, both in vitro and in vivo. YY2201 shows superior in vivo anticancer efficacy and a better therapeutic index compared to AZD6738 in a lung cancer xenograft model. YY2201 also exhibits potent cancer suppression effects in combination with chemotherapy in vivo. Currently, the investigational new drug application of YY2201 has been approved by the FDA for further clinical investigation.ATR is one of the key DNA damage response (DDR) regulatory factors to maintain genome stability. ATR inhibition induces DNA damage accumulation and apoptosis in DDR kinase mutation or deficiency cancer cells through synthetic lethality, making it a promising target for treatment of cancers with DDR defects. Herein, we describe the discovery and preclinical evaluation of YY2201, a highly potent and selective novel ATR inhibitor, with favorable ADME, safety pharmacology, and pharmacokinetics profiles. YY2201 efficiently inhibits tumor progression in broad-spectrum cancer types, both in vitro and in vivo. YY2201 shows superior in vivo anticancer efficacy and a better therapeutic index compared to AZD6738 in a lung cancer xenograft model. YY2201 also exhibits potent cancer suppression effects in combination with chemotherapy in vivo. Currently, the investigational new drug application of YY2201 has been approved by the FDA for further clinical investigation. |
| Author | Wang, Haoran Zheng, Xiao Ye, Xin Chen, Xiaofang Hou, Huimin Liu, Wenjin Weng, Yali Fan, Tianyun Li, Chang Wu, Meng Yang, Jingxin |
| AuthorAffiliation | Jiangsu YaYao Biotechnology Co., Ltd Department of Infectious Diseases Center for Drug Research and Evaluation, National Infrastructures for Translational Medicine, Peking Union Medical College Hospital Department of General Surgery, Peking Union Medical College Hospital Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences & Peking Union Medical College The First Affiliated Hospital of Nanjing Medical University |
| AuthorAffiliation_xml | – name: Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine – name: Department of General Surgery, Peking Union Medical College Hospital – name: Chinese Academy of Medical Sciences & Peking Union Medical College – name: Institute of Medicinal Biotechnology – name: Department of Infectious Diseases – name: Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine – name: Center for Drug Research and Evaluation, National Infrastructures for Translational Medicine, Peking Union Medical College Hospital – name: Jiangsu YaYao Biotechnology Co., Ltd – name: The First Affiliated Hospital of Nanjing Medical University |
| Author_xml | – sequence: 1 givenname: Meng surname: Wu fullname: Wu, Meng organization: Center for Drug Research and Evaluation, National Infrastructures for Translational Medicine, Peking Union Medical College Hospital – sequence: 2 givenname: Xiaofang surname: Chen fullname: Chen, Xiaofang organization: Chinese Academy of Medical Sciences & Peking Union Medical College – sequence: 3 givenname: Haoran surname: Wang fullname: Wang, Haoran organization: Chinese Academy of Medical Sciences & Peking Union Medical College – sequence: 4 givenname: Chang surname: Li fullname: Li, Chang organization: Chinese Academy of Medical Sciences & Peking Union Medical College – sequence: 5 givenname: Wenjin surname: Liu fullname: Liu, Wenjin organization: Jiangsu YaYao Biotechnology Co., Ltd – sequence: 6 givenname: Xiao surname: Zheng fullname: Zheng, Xiao organization: Chinese Academy of Medical Sciences & Peking Union Medical College – sequence: 7 givenname: Jingxin surname: Yang fullname: Yang, Jingxin organization: Chinese Academy of Medical Sciences & Peking Union Medical College – sequence: 8 givenname: Xin surname: Ye fullname: Ye, Xin email: yexinpumch@163.com organization: Chinese Academy of Medical Sciences & Peking Union Medical College – sequence: 9 givenname: Yali surname: Weng fullname: Weng, Yali email: wengyali@njmu.edu.cn organization: The First Affiliated Hospital of Nanjing Medical University – sequence: 10 givenname: Tianyun orcidid: 0000-0001-6770-924X surname: Fan fullname: Fan, Tianyun email: fty1668@163.com organization: Chinese Academy of Medical Sciences & Peking Union Medical College – sequence: 11 givenname: Huimin surname: Hou fullname: Hou, Huimin email: houhuimin0305@163.com organization: Chinese Academy of Medical Sciences & Peking Union Medical College |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/40029060$$D View this record in MEDLINE/PubMed |
| BookMark | eNqNkE1P3DAQhq2KqizQf4AqHyuhbGdsb9Y5ovQDJKQioIc9RY4zYY2yNo0d0P77mu7Csaovc_Dzjt55jtiBD54YO0WYIwj8YmycP2yos2vazJUFITW8YzNcCCiUBnXAZgBCFKIU8pAdxfgAABKF_MAOVf6poIQZW3110YYnGrc89DytideD886agdfGd64zifhqJQQgN5EbfuHu18OWX4dEPvGM8FsayCb3RPz87oZf-rVrXQrjCXvfmyHSx_08Zr--f7urL4qrnz8u6_OrwohqmYqu0lqVWrV91SFW5QLLHltbaaLSdLQoWyE0meXCymoJ1lrsAFqsBGlJxlp5zD7v9j6O4fdEMTWbfBINg_EUpthIXEoFqBVk9NMendpsrnkc3caM2-ZVRwbUDrBjiHGk_g1BaF6sN9l682q92VvPsbNd7Jna0EfryFt6iwKgkmVuAC8PM63_n65dMskFX4fJpxyFXfRvjTCNPpv9d7c_xPenHw |
| Cites_doi | 10.1021/acs.jmedchem.3c01917 10.1038/s41568-022-00535-5 10.1016/j.bioorg.2023.106535 10.1038/nature10760 10.1158/1535-7163.MCT-23-0402 10.1002/jcc.20529 10.3390/molecules29010044 10.1158/0008-5472.CAN-19-3126 10.1038/nrc3891 10.1038/ncomms13837 10.1200/JCO.19.02404 10.1021/acs.jmedchem.8b01187 10.1021/acs.jmedchem.7b00359 10.1016/j.ctrv.2013.03.002 10.1021/acs.jmedchem.0c00369 10.1158/0008-5472.CAN-21-2997 10.1016/j.bmc.2014.02.029 10.1038/s41591-024-02808-y 10.1038/s41571-024-00863-5 10.1038/nrd3845 10.1038/s41588-023-01557-x 10.1158/0008-5472.CAN-16-3398 10.1038/s41388-020-1328-y 10.1038/nrm2450 10.1021/acsmedchemlett.0c00679 10.1016/j.trecan.2021.06.002 10.1158/1078-0432.CCR-23-2409 10.1016/j.celrep.2018.08.019 10.1158/1078-0432.CCR-23-1763 10.1016/j.pharmthera.2019.107450 10.1021/jm070562u 10.1038/s41416-023-02436-2 10.1016/j.molcel.2017.05.015 10.1016/j.biopha.2024.117366 10.1016/j.biopha.2022.114036 10.1016/j.cub.2005.06.012 10.1158/1078-0432.CCR-16-2273 10.1021/acs.orglett.1c01490 10.1021/acs.jcim.1c00203 10.1016/j.jmb.2017.04.006 10.1002/jcc.21334 10.1128/MCB.21.13.4129-4139.2001 |
| ContentType | Journal Article |
| Copyright | 2025 American Chemical Society |
| Copyright_xml | – notice: 2025 American Chemical Society |
| DBID | 17B 1KM BLEPL DTL EGQ AAYXX CITATION CGR CUY CVF ECM EIF NPM 7X8 |
| DOI | 10.1021/acs.jmedchem.4c02380 |
| DatabaseName | Web of Knowledge Index Chemicus Web of Science Core Collection Science Citation Index Expanded Web of Science Primary (SCIE, SSCI & AHCI) CrossRef Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic |
| DatabaseTitle | Web of Science CrossRef MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic |
| DatabaseTitleList | MEDLINE Web of Science MEDLINE - Academic |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 1KM name: Index Chemicus url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/woscc/search-with-editions?editions=WOS.IC sourceTypes: Enrichment Source Index Database |
| DeliveryMethod | fulltext_linktorsrc |
| Discipline | Chemistry Pharmacy, Therapeutics, & Pharmacology |
| EISSN | 1520-4804 |
| EndPage | 5311 |
| ExternalDocumentID | 40029060 10_1021_acs_jmedchem_4c02380 001436018000001 b334760735 |
| Genre | Journal Article |
| GrantInformation_xml | – fundername: Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences – fundername: National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) grantid: BJ-2022-096; BJ-2022-143; 2022-PUMCH-A-051 – fundername: National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) grantid: 2023-JKCS-22 – fundername: Biomedical Engineering Facility, National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College – fundername: Jiangsu YaYao Biotechnology Co., Ltd. – fundername: National High Level Hospital Clinical Research Funding grantid: 82104231; 82104013; 82273781 |
| GroupedDBID | --- -~X .K2 4.4 55A 5GY 5RE 5VS 6P2 7~N AABXI AAHBH ABJNI ABMVS ABOCM ABQRX ABTAH ABUCX ACGFO ACGFS ACJ ACS ADHLV AEESW AENEX AFEFF AGXLV AHGAQ ALMA_UNASSIGNED_HOLDINGS AQSVZ BAANH CS3 CUPRZ DU5 EBS ED~ F5P GGK GNL IH2 IH9 IHE JG~ L7B LG6 P2P ROL TN5 UI2 VF5 VG9 W1F WH7 XSW YQT YZZ ZY4 17B 1KM ABBLG ABLBI BLEPL DTL GROUPED_WOS_WEB_OF_SCIENCE AAYXX CITATION CGR CUY CVF ECM EIF NPM 7X8 |
| ID | FETCH-LOGICAL-a297t-d9884684bf9d1196516f1bc98ee6ade56b228ea75c3970ccc1d00b192e83eacc3 |
| IEDL.DBID | ACS |
| ISICitedReferencesCount | 2 |
| ISICitedReferencesURI | https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestApp=WOS&DestLinkType=CitingArticles&UT=001436018000001 |
| ISSN | 0022-2623 1520-4804 |
| IngestDate | Thu Jul 10 19:10:04 EDT 2025 Fri Mar 14 02:03:00 EDT 2025 Tue Jul 01 05:21:24 EDT 2025 Fri Aug 29 16:18:04 EDT 2025 Mon Jul 21 06:54:11 EDT 2025 Fri Mar 14 03:10:57 EDT 2025 |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 5 |
| Keywords | ATAXIA-TELANGIECTASIA DNA-DAMAGE RESPONSE OPTIMIZATION |
| Language | English |
| License | https://doi.org/10.15223/policy-029 https://doi.org/10.15223/policy-037 https://doi.org/10.15223/policy-045 |
| LinkModel | DirectLink |
| LogoURL | https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg |
| MergedId | FETCHMERGED-LOGICAL-a297t-d9884684bf9d1196516f1bc98ee6ade56b228ea75c3970ccc1d00b192e83eacc3 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ORCID | 0000-0001-6770-924X |
| PMID | 40029060 |
| PQID | 3173401840 |
| PQPubID | 23479 |
| PageCount | 20 |
| ParticipantIDs | pubmed_primary_40029060 acs_journals_10_1021_acs_jmedchem_4c02380 proquest_miscellaneous_3173401840 crossref_primary_10_1021_acs_jmedchem_4c02380 webofscience_primary_001436018000001 webofscience_primary_001436018000001CitationCount |
| ProviderPackageCode | CITATION AAYXX |
| PublicationCentury | 2000 |
| PublicationDate | 2025-03-13 |
| PublicationDateYYYYMMDD | 2025-03-13 |
| PublicationDate_xml | – month: 03 year: 2025 text: 2025-03-13 day: 13 |
| PublicationDecade | 2020 |
| PublicationPlace | WASHINGTON |
| PublicationPlace_xml | – name: WASHINGTON – name: United States |
| PublicationTitle | Journal of medicinal chemistry |
| PublicationTitleAbbrev | J MED CHEM |
| PublicationTitleAlternate | J. Med. Chem |
| PublicationYear | 2025 |
| Publisher | American Chemical Society Amer Chemical Soc |
| Publisher_xml | – name: American Chemical Society – name: Amer Chemical Soc |
| References | Mutreja, K (WOS:000443588800012) 2018; 24 Duan, YX (WOS:000984621100001) 2023; 136 Yap, TA (WOS:000574579100010) 2020; 38 Lloyd, RL (WOS:000534868800001) 2020; 39 Miwa, S (WOS:000651790900011) 2021; 12 Kim, H (WOS:000403330000026) 2017; 23 Lücking, U (WOS:000550753700043) 2020; 63 Black, WC (WOS:001160926900001) 2024; 67 Bowes, J (WOS:000311895800019) 2012; 11 Fokas, E (WOS:000328871200013) 2014; 40 Ryan, CJ (WOS:001111853400001) 2023; 55 Hiom, K (WOS:000230189100021) 2005; 15 Tian, Y (WOS:000334337800006) 2014; 22 Besse, B (WOS:001161800900002) 2024; 30 Truhlar, DG (WOS:000243171300008) 2007; 28 Williamson, CT (WOS:000389671100003) 2016; 7 Graczyk, PP (WOS:000250809300031) 2007; 50 Yap, TA (WOS:001223351000011) 2024; 30 Jo, U (WOS:001262123800006) 2024; 23 Pearl, LH (WOS:000350296100010) 2015; 15 Rafiei, S (WOS:000537843200005) 2020; 80 Cimprich, KA (WOS:000257882000014) 2008; 9 Eberhardt, J (WOS:000688241800015) 2021; 61 Tellal, S (WOS:001141451700001) 2024; 29 Chen, X (WOS:001306880300001) 2024; 179 Lord, CJ (WOS:000299210600030) 2012; 481 Wilson, Z (WOS:000772155800001) 2022; 82 McCoull, W (WOS:000402498200021) 2017; 60 Schmitt, A (WOS:000402546200025) 2017; 77 Ngoi, NYL (WOS:001168925200001) 2024; 21 Bradbury, A (WOS:000520609600001) 2020; 207 Zhao, H (WOS:000169233400005) 2001; 21 Burris, HA (WOS:001153707800001) 2024; 130 Groelly, FJ (WOS:000894377700001) 2023; 23 Guo, SH (WOS:000911301400008) 2023; 157 Lu, YP (WOS:000403623500007) 2017; 429 Foote, KM (WOS:000451496300005) 2018; 61 Morales-Colón, MT (WOS:000661126700078) 2021; 23 Pilie, PG (WOS:001223351000019) 2024; 30 Blackford, AN (WOS:000403329400009) 2017; 66 Ngoi, NYL (WOS:000698790800007) 2021; 7 ref9/cit9 ref6/cit6 ref36/cit36 ref3/cit3 ref27/cit27 ref18/cit18 ref11/cit11 ref25/cit25 ref16/cit16 ref29/cit29 ref32/cit32 ref23/cit23 ref39/cit39 ref14/cit14 ref8/cit8 ref5/cit5 ref31/cit31 ref2/cit2 ref34/cit34 ref37/cit37 ref28/cit28 ref40/cit40 ref20/cit20 ref17/cit17 ref10/cit10 ref26/cit26 ref35/cit35 ref19/cit19 ref21/cit21 ref12/cit12 ref15/cit15 ref41/cit41 ref22/cit22 ref13/cit13 ref33/cit33 ref4/cit4 ref30/cit30 ref1/cit1 ref24/cit24 ref38/cit38 ref7/cit7 |
| References_xml | – volume: 67 start-page: 2349 year: 2024 ident: WOS:001160926900001 article-title: Discovery of the Potent and Selective ATR Inhibitor Camonsertib (RP-3500) publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/acs.jmedchem.3c01917 – volume: 23 start-page: 78 year: 2023 ident: WOS:000894377700001 article-title: Targeting DNA damage response pathways in cancer publication-title: NATURE REVIEWS CANCER doi: 10.1038/s41568-022-00535-5 – volume: 136 start-page: ARTN 106535 year: 2023 ident: WOS:000984621100001 article-title: Design, synthesis, and biological evaluation of pyrido[3,2-d]pyrimidine derivatives as novel ATR inhibitors publication-title: BIOORGANIC CHEMISTRY doi: 10.1016/j.bioorg.2023.106535 – volume: 481 start-page: 287 year: 2012 ident: WOS:000299210600030 article-title: The DNA damage response and cancer therapy publication-title: NATURE doi: 10.1038/nature10760 – volume: 23 start-page: 911 year: 2024 ident: WOS:001262123800006 article-title: The Novel ATR Inhibitor M1774 Induces Replication Protein Overexpression and Broad Synergy with DNA-targeted Anticancer Drugs publication-title: MOLECULAR CANCER THERAPEUTICS doi: 10.1158/1535-7163.MCT-23-0402 – volume: 28 start-page: 73 year: 2007 ident: WOS:000243171300008 article-title: Valence bond theory for chemical dynamics publication-title: JOURNAL OF COMPUTATIONAL CHEMISTRY doi: 10.1002/jcc.20529 – volume: 29 start-page: ARTN 44 year: 2024 ident: WOS:001141451700001 article-title: Synthesis of Trifluoromethylated Pyrimido[1,2-b]indazole Derivatives through the Cyclocondensation of 3-Aminoindazoles with Ketoester and Their Functionalization via Suzuki-Miyaura Cross-Coupling and SNAr Reactions publication-title: MOLECULES doi: 10.3390/molecules29010044 – volume: 80 start-page: 2094 year: 2020 ident: WOS:000537843200005 article-title: ATM Loss Confers Greater Sensitivity to ATR Inhibition Than PARP Inhibition in Prostate Cancer publication-title: CANCER RESEARCH doi: 10.1158/0008-5472.CAN-19-3126 – volume: 15 start-page: 166 year: 2015 ident: WOS:000350296100010 article-title: Therapeutic opportunities within the DNA damage response publication-title: NATURE REVIEWS CANCER doi: 10.1038/nrc3891 – volume: 7 start-page: ARTN 13837 year: 2016 ident: WOS:000389671100003 article-title: ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A publication-title: NATURE COMMUNICATIONS doi: 10.1038/ncomms13837 – volume: 38 start-page: 3195 year: 2020 ident: WOS:000574579100010 article-title: Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors publication-title: JOURNAL OF CLINICAL ONCOLOGY doi: 10.1200/JCO.19.02404 – volume: 61 start-page: 9889 year: 2018 ident: WOS:000451496300005 article-title: Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/acs.jmedchem.8b01187 – volume: 21 start-page: 4129 year: 2001 ident: WOS:000169233400005 article-title: ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1 publication-title: MOLECULAR AND CELLULAR BIOLOGY – volume: 60 start-page: 4386 year: 2017 ident: WOS:000402498200021 article-title: Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/acs.jmedchem.7b00359 – volume: 40 start-page: 109 year: 2014 ident: WOS:000328871200013 article-title: Targeting ATR in DNA damage response and cancer therapeutics publication-title: CANCER TREATMENT REVIEWS doi: 10.1016/j.ctrv.2013.03.002 – volume: 63 start-page: 7293 year: 2020 ident: WOS:000550753700043 article-title: Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/acs.jmedchem.0c00369 – volume: 82 start-page: 1140 year: 2022 ident: WOS:000772155800001 article-title: ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity as a Monotherapy and in Combination with Chemotherapy and the PARP Inhibitor Olaparib publication-title: CANCER RESEARCH doi: 10.1158/0008-5472.CAN-21-2997 – volume: 22 start-page: 2052 year: 2014 ident: WOS:000334337800006 article-title: Fused heterocyclic compounds bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 1: Design, synthesis and biological evaluation of novel 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives publication-title: BIOORGANIC & MEDICINAL CHEMISTRY doi: 10.1016/j.bmc.2014.02.029 – volume: 30 start-page: 716 year: 2024 ident: WOS:001161800900002 article-title: Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial publication-title: NATURE MEDICINE doi: 10.1038/s41591-024-02808-y – volume: 21 start-page: 278 year: 2024 ident: WOS:001168925200001 article-title: Targeting ATR in patients with cancer publication-title: NATURE REVIEWS CLINICAL ONCOLOGY doi: 10.1038/s41571-024-00863-5 – volume: 11 start-page: 909 year: 2012 ident: WOS:000311895800019 article-title: Reducing safety-related drug attrition: the use of in vitro pharmacological profiling publication-title: NATURE REVIEWS DRUG DISCOVERY doi: 10.1038/nrd3845 – volume: 55 start-page: 2025 year: 2023 ident: WOS:001111853400001 article-title: Complex synthetic lethality in cancer publication-title: NATURE GENETICS doi: 10.1038/s41588-023-01557-x – volume: 77 start-page: 3040 year: 2017 ident: WOS:000402546200025 article-title: ATM Deficiency Is Associated with Sensitivity to PARP1-and ATR Inhibitors in Lung Adenocarcinoma publication-title: CANCER RESEARCH doi: 10.1158/0008-5472.CAN-16-3398 – volume: 39 start-page: 4869 year: 2020 ident: WOS:000534868800001 article-title: Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells publication-title: ONCOGENE doi: 10.1038/s41388-020-1328-y – volume: 9 start-page: 616 year: 2008 ident: WOS:000257882000014 article-title: ATR: an essential regulator of genome integrity publication-title: NATURE REVIEWS MOLECULAR CELL BIOLOGY doi: 10.1038/nrm2450 – volume: 12 start-page: 745 year: 2021 ident: WOS:000651790900011 article-title: Discovery of Selective Transforming Growth Factor β Type II Receptor Inhibitors as Antifibrosis Agents publication-title: ACS MEDICINAL CHEMISTRY LETTERS doi: 10.1021/acsmedchemlett.0c00679 – volume: 7 start-page: 930 year: 2021 ident: WOS:000698790800007 article-title: Targeting the replication stress response through synthetic lethal strategies in cancer medicine publication-title: TRENDS IN CANCER doi: 10.1016/j.trecan.2021.06.002 – volume: 30 start-page: 2057 year: 2024 ident: WOS:001223351000011 article-title: First-in-Human Study of the Ataxia Telangiectasia and Rad3-Related (ATR) Inhibitor Tuvusertib (M1774) as Monotherapy in Patients with Solid Tumors publication-title: CLINICAL CANCER RESEARCH doi: 10.1158/1078-0432.CCR-23-2409 – volume: 24 start-page: 2629 year: 2018 ident: WOS:000443588800012 article-title: ATR-Mediated Global Fork Slowing and Reversal Assist Fork Traverse and Prevent Chromosomal Breakage at DNA Interstrand Cross-Links publication-title: CELL REPORTS doi: 10.1016/j.celrep.2018.08.019 – volume: 30 start-page: 2121 year: 2024 ident: WOS:001223351000019 article-title: Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types publication-title: CLINICAL CANCER RESEARCH doi: 10.1158/1078-0432.CCR-23-1763 – volume: 207 start-page: ARTN 107450 year: 2020 ident: WOS:000520609600001 article-title: Targeting ATR as Cancer Therapy: A new era for synthetic lethality and synergistic combinations? publication-title: PHARMACOLOGY & THERAPEUTICS doi: 10.1016/j.pharmthera.2019.107450 – volume: 50 start-page: 5773 year: 2007 ident: WOS:000250809300031 article-title: Gini coefficient: A new way to express selectivity of kinase inhibitors against a family of kinases publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/jm070562u – volume: 130 start-page: 1131 year: 2024 ident: WOS:001153707800001 article-title: A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours publication-title: BRITISH JOURNAL OF CANCER doi: 10.1038/s41416-023-02436-2 – volume: 66 start-page: 801 year: 2017 ident: WOS:000403329400009 article-title: ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response publication-title: MOLECULAR CELL doi: 10.1016/j.molcel.2017.05.015 – volume: 179 start-page: ARTN 117366 year: 2024 ident: WOS:001306880300001 article-title: METTL3 inhibitor suppresses the progression of prostate cancer via IGFBP3/AKT pathway and synergizes with PARP inhibitor publication-title: BIOMEDICINE & PHARMACOTHERAPY doi: 10.1016/j.biopha.2024.117366 – volume: 157 start-page: ARTN 114036 year: 2023 ident: WOS:000911301400008 article-title: Genomic instability drives tumorigenesis and metastasis and its implications for cancer therapy publication-title: BIOMEDICINE & PHARMACOTHERAPY doi: 10.1016/j.biopha.2022.114036 – volume: 15 start-page: R473 year: 2005 ident: WOS:000230189100021 article-title: DNA repair: How to PIKK a partner publication-title: CURRENT BIOLOGY doi: 10.1016/j.cub.2005.06.012 – volume: 23 start-page: 3097 year: 2017 ident: WOS:000403330000026 article-title: Targeting the ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression in BRCA-Mutant Ovarian Cancer Models publication-title: CLINICAL CANCER RESEARCH doi: 10.1158/1078-0432.CCR-16-2273 – volume: 23 start-page: 4493 year: 2021 ident: WOS:000661126700078 article-title: Tetramethylammonium Fluoride Alcohol Adducts for SNAr Fluorination publication-title: ORGANIC LETTERS doi: 10.1021/acs.orglett.1c01490 – volume: 61 start-page: 3891 year: 2021 ident: WOS:000688241800015 article-title: AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings publication-title: JOURNAL OF CHEMICAL INFORMATION AND MODELING doi: 10.1021/acs.jcim.1c00203 – volume: 429 start-page: 1684 year: 2017 ident: WOS:000403623500007 article-title: Rationally Designed PI3Kα Mutants to Mimic ATR and Their Use to Understand Binding Specificity of ATR Inhibitors publication-title: JOURNAL OF MOLECULAR BIOLOGY doi: 10.1016/j.jmb.2017.04.006 – ident: ref31/cit31 doi: 10.1016/j.bmc.2014.02.029 – ident: ref33/cit33 doi: 10.3390/molecules29010044 – ident: ref29/cit29 doi: 10.1021/acs.jmedchem.7b00359 – ident: ref40/cit40 doi: 10.1016/j.biopha.2024.117366 – ident: ref21/cit21 doi: 10.1158/1078-0432.CCR-23-2409 – ident: ref38/cit38 doi: 10.1021/acs.jcim.1c00203 – ident: ref8/cit8 doi: 10.1016/j.cub.2005.06.012 – ident: ref27/cit27 doi: 10.1158/1535-7163.MCT-23-0402 – ident: ref28/cit28 doi: 10.1016/j.bioorg.2023.106535 – ident: ref15/cit15 doi: 10.1038/ncomms13837 – ident: ref25/cit25 doi: 10.1021/acs.jmedchem.3c01917 – ident: ref41/cit41 doi: 10.1021/jm070562u – ident: ref11/cit11 doi: 10.1016/j.celrep.2018.08.019 – ident: ref16/cit16 doi: 10.1158/0008-5472.CAN-19-3126 – ident: ref24/cit24 doi: 10.1021/acs.jmedchem.8b01187 – ident: ref23/cit23 doi: 10.1021/acs.jmedchem.0c00369 – ident: ref9/cit9 doi: 10.1016/j.trecan.2021.06.002 – ident: ref10/cit10 doi: 10.1038/nrm2450 – ident: ref2/cit2 doi: 10.1038/nature10760 – ident: ref37/cit37 doi: 10.1158/0008-5472.CAN-21-2997 – ident: ref5/cit5 doi: 10.1038/nrc3891 – ident: ref3/cit3 doi: 10.1038/s41568-022-00535-5 – ident: ref19/cit19 doi: 10.1016/j.pharmthera.2019.107450 – ident: ref36/cit36 doi: 10.1038/s41591-024-02808-y – ident: ref26/cit26 doi: 10.1158/1078-0432.CCR-23-1763 – ident: ref6/cit6 doi: 10.1038/s41571-024-00863-5 – ident: ref35/cit35 doi: 10.1038/nrd3845 – ident: ref7/cit7 doi: 10.1016/j.molcel.2017.05.015 – ident: ref18/cit18 doi: 10.1158/1078-0432.CCR-16-2273 – ident: ref32/cit32 doi: 10.1021/acs.orglett.1c01490 – ident: ref14/cit14 doi: 10.1158/0008-5472.CAN-16-3398 – ident: ref22/cit22 doi: 10.1038/s41416-023-02436-2 – ident: ref17/cit17 doi: 10.1038/s41388-020-1328-y – ident: ref39/cit39 doi: 10.1002/jcc.21334 – ident: ref4/cit4 doi: 10.1038/s41588-023-01557-x – ident: ref12/cit12 doi: 10.1128/MCB.21.13.4129-4139.2001 – ident: ref1/cit1 doi: 10.1016/j.biopha.2022.114036 – ident: ref34/cit34 doi: 10.1016/j.jmb.2017.04.006 – ident: ref13/cit13 doi: 10.1016/j.ctrv.2013.03.002 – ident: ref20/cit20 doi: 10.1200/JCO.19.02404 – ident: ref30/cit30 doi: 10.1021/acsmedchemlett.0c00679 |
| SSID | ssj0003123 |
| Score | 2.4816968 |
| Snippet | ATR is one of the key DNA damage response (DDR) regulatory factors to maintain genome stability. ATR inhibition induces DNA damage accumulation and apoptosis... |
| Source | Web of Science |
| SourceID | proquest pubmed crossref webofscience acs |
| SourceType | Aggregation Database Index Database Enrichment Source Publisher |
| StartPage | 5292 |
| SubjectTerms | Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors Ataxia Telangiectasia Mutated Proteins - metabolism Cell Line, Tumor Chemistry, Medicinal Drug Discovery Female Humans Life Sciences & Biomedicine Male Mice Mice, Nude Pharmacology & Pharmacy Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacokinetics Pyrimidines - pharmacology Pyrimidines - therapeutic use Rats Science & Technology Structure-Activity Relationship Xenograft Model Antitumor Assays |
| Title | Discovery of the Clinical Candidate YY2201 as a Highly Potent and Selective ATR Inhibitor |
| URI | http://dx.doi.org/10.1021/acs.jmedchem.4c02380 http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestApp=WOS&DestLinkType=FullRecord&UT=001436018000001 https://www.ncbi.nlm.nih.gov/pubmed/40029060 https://www.proquest.com/docview/3173401840 |
| Volume | 68 |
| WOS | 001436018000001 |
| WOSCitedRecordID | wos001436018000001 |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwlV1Zb9QwEB6h8gAvHOVaLg1SVQmpWeJjczxWgaogASu6lbpPke04aqFkUZN9WH49Mzl2gYIor7FlyeOx55vMzDcAO3QJEuNKOoEoLQJd-DIwhBwCHVnplA3j2HI18vsP0eGxfncyOdk4ir9H8KV4ZVw9_szJiqf-61g7tjHkol-XESFthkLZ0frlVUKqgR1ckl0fSuX-sgobJFf_apAuocw_GqTW-Bzcho9DCU-Xc_JlvGzs2H2_zOh4xX3dgVs9DsX9TnHuwjVfbcONbGj_tg27047UerWHs02NVr2Huzjd0F2v7sH89VntOBF0hYsSCU9izzV6jhnXzPAvBZzPJWEANDUa5NSS8xVOFwTXG6QpeNQ246F3F_dnn_BtdXpm6aG5uA_HB29m2WHQN2wIjEzjJijShOBMom2ZFoKpCkVUCuvSxPvIFH5C5y8Tb-KJIxQUOudEEYaWMKZPFBkApx7AVrWo_CPA0snYiELReKi18algX7TQ5C2ljlykEbwkAeb9havzNpYuRd5-7KWa91IdQTCccP6t4_D4x_wXgxrkJHSOoJjKL5Z1TmBLkUNKTvEIHnb6sV5Rc4AzjGhk52eFWY-zM6oi5ktrIyojEFeZlvVM7cxQ0Dz-j00_gZuSWxVz6qF6ClvNxdI_I_zU2OftpfkBiwETSg |
| linkProvider | American Chemical Society |
| linkToHtml | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwlV1Zb9swDCaK7qF72dFd2ckBRYEBdWbJio_HwFuRbm0RrOnQPBmSLKPdOmeonYfs14907GQntr5agqCDEj-a5EeAHboEsbYFnUCY5J7KXeFpQg6eCo20gfGjyHA28tFxODpV784GZxsw6HJhaBIVjVQ1Tvw1u4B4zd8-ccziufvSV5ZVDVnqNwiPSI7kG6Ynqwc4EDLoSMIlqfcuY-4vo7BestXPeuk3sPlHvdTooP3b8HE1-yb05HN_Xpu-_fYLseO1l3cHbrWoFIdLMboLG67chq20Kwa3DbvjJcX1Yg8n64ytag93cbwmv17cg-mbi8pyWOgCZwUSusSWefQSU86g4R8MOJ1KQgSoK9TIgSaXCxzPCLzXSF3wpCnNQ68wDicf8KA8vzD07Fzdh9P9t5N05LXlGzwtk6j28iQmcBMrUyS5YOJCERbC2CR2LtS5G5A0yNjpaGAJE_nWWpH7viHE6eKA1IENHsBmOSvdI8DCykiLPKB2XyntEsGWaa7IdkosGUw9eEUbmLXXr8oaz7oUWfOx3dWs3dUeeN1BZ1-XjB7_6P-yk4aMNp39Kbp0s3mVEfQKyDwlE7kHD5dishpRsbvTD6ll50e5WbWzaRqEzJ7W-Fd6IP6nW9rytjNfQf34Got-AVujydFhdnhw_P4J3JRcxJiDEoOnsFlfzd0zQla1ed7co-_Hthur |
| linkToPdf | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1Za9tAEB5KCm1feqSXe24hBAqRqz2s49EoNUmPYBoH4r6IvUSuyiGSH9xf3xlZctKLHq-7y6Ldnd35RjPzDcAGXoJE2wJPIEpdoJwvAo3IIVCREVaaMI4NZSN_3It2DtS7w8HhlVJf-BEVzlQ1Tny61eeuaBkG-BtqP6G4xSP_pa8sqRu01q-T546i-YbZ_uoRllzIjihcoIrvsuZ-MwvpJlt9r5t-Apy_1E2NHhrdgc-rFTThJ6f9eW369usP5I7_tcS7cLtFp2y4FKd7cM2X63Az64rCrcPmeEl1vdhik8vMrWqLbbLxJQn24j5Mt48rS-GhCzYrGKJM1jKQnrGMMmnoRwObTgUiA6YrphkFnJwt2HiGIL5mOITtNyV68DVmw8kntlseHRt8fi4ewMHo7STbCdoyDoEWaVwHLk0Q5CTKFKnjRGDIo4IbmybeR9r5AUqFSLyOBxaxUWit5S4MDSJPn0hUC1Y-hLVyVvrHwAorYs2dxP5QKe1TThaqU2hDpRYNpx68xg3M22tY5Y2HXfC8aWx3NW93tQdBd9j5-ZLZ4w_jX3USkeOmk19Fl342r3KEYBLNVDSVe_BoKSqrGRW5PcMIezauys6qn0xUGRGLWuNn6QH_m2FZy99OvAX1k39Y9Eu4Md4e5R92994_hVuCahlTbKJ8Bmv1xdw_R4BVmxfNVfoG-qEeLg |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Discovery+of+the+Clinical+Candidate+YY2201+as+a+Highly+Potent+and+Selective+ATR+Inhibitor&rft.jtitle=Journal+of+medicinal+chemistry&rft.au=Wu%2C+Meng&rft.au=Chen%2C+Xiaofang&rft.au=Wang%2C+Haoran&rft.au=Li%2C+Chang&rft.date=2025-03-13&rft.pub=American+Chemical+Society&rft.issn=0022-2623&rft.eissn=1520-4804&rft.volume=68&rft.issue=5&rft.spage=5292&rft.epage=5311&rft_id=info:doi/10.1021%2Facs.jmedchem.4c02380&rft.externalDocID=b334760735 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0022-2623&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0022-2623&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0022-2623&client=summon |