Discovery of PROTAC BCL-X-L degraders as potent anticancer agents with low on-target platelet toxicity

• Published in: European journal of medicinal chemistry Vol. 192; pp. 112186 - 112209
• Main Authors: Zhang, Xuan, Thummuri, Dinesh, Liu, Xingui, Hu, Wanyi, Zhang, Peiyi, Khan, Sajid, Yuan, Yaxia, Zhou, Daohong, Zheng, Guangrong
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier 15.04.2020
• Subjects: Aniline Compounds - chemical synthesis; Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; bcl-X Protein - antagonists & inhibitors; Blood Platelets - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry, Medicinal; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Proteolysis - drug effects; Science & Technology; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Tumor Cells, Cultured; BCL-X-L; PROTAC; IDENTIFICATION; CANCER; COMPLETE TUMOR-REGRESSION; FAMILY; Degradation; INDUCED PROTEIN-DEGRADATION; Platelet; VENETOCLAX; SENESCENT CELLS; INHIBITOR; NAVITOCLAX; Apoptosis; BCL-X(L)
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112186

Anti-apoptotic protein BCL-X-L plays a key role in tumorigenesis and cancer chemotherapy resistance, rendering it an attractive target for cancer treatment. However, BCL-X-L inhibitors such as ABT-263 cannot be safely used in the clinic because platelets solely depend on BCL-X-L to maintain their viability. To reduce the on-target platelet toxicity associated with the inhibition of BCL-X-L, we designed and synthesized PROTAC BCL-X-L degraders that recruit CRBN or VHL E3 ligase because both of these enzymes are poorly expressed in human platelets compared to various cancer cell lines. We confirmed that platelet-toxic BCL-X-L/2 dual inhibitor ABT-263 can be converted into platelet-sparing CRBN/VHL-based BCL-X-L specific degraders. A number of BCL-X-L degraders are more potent in killing cancer cells than their parent compound ABT-263. Specifically, XZ739, a CRBN-dependent BCL-X-L degrader, is 20-fold more potent than ABT-263 against MOLT-4 T-ALL cells and has >100-fold selectivity for MOLT-4 cells over human platelets. Our findings further demonstrated the utility of PROTAC technology to achieve tissue selectivity through recruiting differentially expressed E3 ligases. (c) 2020 Elsevier Masson SAS. All rights reserved.