Drug-like property optimization: Discovery of orally bioavailable quinazoline-based multi-targeted kinase inhibitors

Shu Yu Lin, Chun Feng Chang, Mohane Selvaraj Coumar, Pei Yi Chen, Fu Ming Kuo, Chun Hwa Chen, Mu Chun Li, Wen Hsing Lin, Po Chu Kuo, Sing Yi Wang, An Siou Li, Chin Yu Lin, Chen Ming Yang, Teng Kuang Yeh, Jen Shin Song, John T.A. Hsu, Hsing Pang Hsieh

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

In an effort to develop new cancer therapeutics, we have reported clinical candidate BPR1K871 (1) as a potent anticancer compound in MOLM-13 and MV4-11 leukemia models, as well as in colorectal and pancreatic animal models. As BPR1K871 lacks oral bioavailability, we continued searching for orally bioavailable analogs through drug-like property optimization. We optimized both the physicochemical properties (PCP) as well as in vitro rat liver microsomal stability of 1, with concomitant monitoring of aurora kinase enzyme inhibition as well as cellular anti-proliferative activity in HCT-116 cell line. Structural modification at the 6- and 7-position of quinazoline core of 1 led to the identification of 34 as an orally bioavailable (F% = 54) multi-kinase inhibitor, which exhibits potent anti-proliferative activity against various cancer cell lines. Quinazoline 34 is selected as a promising oral lead candidate for further preclinical evaluation.

Original languageEnglish
Article number103689
JournalBioorganic Chemistry
Volume98
DOIs
Publication statusPublished - 2020 May

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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