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

Shu-Yu Lin1, Chun-Feng Chang1, Mohane Selvaraj Coumar2

  • 1Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan, ROC.

Bioorganic Chemistry
|March 16, 2020
PubMed

Insights

Researchers developed an orally bioavailable cancer therapeutic by optimizing a compound

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Drug Discovery

Background:

  • BPR1K871 is a potent anticancer compound but lacks oral bioavailability.
  • Optimization of drug-like properties is crucial for developing orally administered cancer therapeutics.

Purpose of the Study:

  • To identify orally bioavailable analogs of BPR1K871.
  • To optimize physicochemical properties and in vitro stability while maintaining anticancer activity.

Main Methods:

  • Structural modifications of the quinazoline core of BPR1K871.
  • Evaluation of physicochemical properties, in vitro rat liver microsomal stability, aurora kinase inhibition, and anti-proliferative activity in HCT-116 cells.

Main Results:

  • Identification of quinazoline 34 as an orally bioavailable (F% = 54) multi-kinase inhibitor.
  • Compound 34 demonstrated potent anti-proliferative activity against various cancer cell lines.

Conclusions:

  • Quinazoline 34 represents a promising oral lead candidate for further preclinical development.
  • Drug-like property optimization successfully yielded an orally bioavailable anticancer agent.
Keywords:
Anti-cancerAurora kinase inhibitorMetabolic stabilityOral bioavailabilityPhysicochemical propertyQuinazoline

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