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Drug-like property optimization: Discovery of orally bioavailable quinazoline-based multi-targeted kinase inhibitors.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2020 May; Vol. 98, pp. 103689. Date of Electronic Publication: 2020 Feb 21. - Publication Year :
- 2020
-
Abstract
- In an effort to develop new cancer therapeutics, we have reported clinical candidate BPR1K871 (1) as a potentanticancercompound 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.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Administration, Oral
Animals
Antineoplastic Agents administration & dosage
Antineoplastic Agents chemistry
Aurora Kinases metabolism
Biological Availability
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HCT116 Cells
Humans
Male
Molecular Structure
Protein Kinase Inhibitors administration & dosage
Protein Kinase Inhibitors chemistry
Quinazolines administration & dosage
Quinazolines chemistry
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Antineoplastic Agents pharmacology
Aurora Kinases antagonists & inhibitors
Drug Discovery
Protein Kinase Inhibitors pharmacology
Quinazolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 98
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32171993
- Full Text :
- https://doi.org/10.1016/j.bioorg.2020.103689