Discovery and optimization of tetrahydropyrido[4,3-d]pyrimidine derivatives as novel ATX and EGFR dual inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 8; pp. 1784 - 1796
• Main Authors: Jing, Tongfei, Miao, Xiuqi, Jiang, Feng, Guo, Ming, Xing, Lingyun, Zhang, Junlong, Zuo, Daiying, Lei, Hongrui, Zhai, Xin
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.05.2018; Elsevier
• Subjects: ATX; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; EGFR; Inhibitor; IPF-LC; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Semicarbazones; THPPs; Inhibitor; Semicarbazones; IPF-LC; ATX; THPPs; EGFR; DESIGN; TYROSINE KINASES; PHASE-3; LUNG-CANCER; PATHWAY; IDIOPATHIC PULMONARY-FIBROSIS; AUTOTAXIN; BINDING; SCAFFOLD
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.02.023

[Display omitted] •A series of novel THPPs derivatives (7a–7 m, 8a–8 k &9a–9f) were designed and synthesized.•9a showed better cytotoxicity and anti-fibrosis activity against tested cells than positive control.•Enzymatic assays ascertained 9a with promising EGFR (24.2 nM) and ATX (29.1 nM) inhibitory potency.•RT-PCR study revealed 9a could reduce the mRNA expression of TGF-β and TNF-α significantly.•Docking mode indicated 9a could form critical bonding interactions with both of EGFR and ATX. In order to discovery autotaxin (ATX) and EGFR dual inhibitors with potential therapeutic effect on IPF-LC, a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives possessing semicarbazones moiety were designed and synthesized. The preliminary investigation at the cellular level indicated six compounds (7h, 8a, 8c, 8d, 9a and 9d) displayed preferable anti-tumor activities against A549, H1975, MKN-45 and SGC cancer cells. Further enzymatic assay against EGFR kinase identified 8a and 9a as promising hits with IC50 values of 18.0 nM and 24.2 nM. Meanwhile, anti-inflammatory assessment against cardiac fibroblasts (CFs) cell and RAW264.7 macrophages led to the discovery of candidate 9a, which exhibited considerable potency both on inhibition rate of 77% towards CFs and on reducing NO production to 1.05 μM at 10 μg/mL. Simultaneously, 9a indicated preferable potency towards ATX with IC50 value of 29.1 nM. Significantly, a RT-PCR study revealed the function of 9a to down-regulate the mRNA expression of TGF-β and TNF-α in a dose-dependent manner. The molecular docking analysis together with the pharmacological studies validated 9a as a potential ATX and EGFR dual inhibitor for IPF-LC treatments.