Design and synthesis of boron-containing ALK inhibitor with favorable in vivo efficacy

Bioorg Med Chem. 2022 Dec 1:75:117071. doi: 10.1016/j.bmc.2022.117071. Epub 2022 Oct 25.

Abstract

ALK is an attractive therapeutic target for the treatment of non-small cell lung cancer. As an emerging element in medicinal chemistry, boron has achieved great success in the discovery of antitumor drugs and antibacterial agents. Through construction of a BCC (boron-containing compound) compound library and broad kinase screening, we found the ALK inhibitor hit compound 10a. Structural optimization by CADD and isosterism revealed that lead compound 10k has improved activity (ALKL1196M IC50 = 8.4 nM, NCI-H2228 cells IC50 = 520 nM) and better in vitro metabolic stability (human liver microsomes, T1/2 = 238 min). Compound 10k showed good in vivo efficacy in a nude mouse NCI-H2228 lung cancer xenograft model with a TGI of 52 %. Molecular simulation analysis results show that the hydroxyl group on the oxaborole forms a key hydrogen bond with Asn1254 or Asp1270, and this binding site provides a new idea for drug design. This is the first publicly reported lead compound for a boron-containing ALK inhibitor.

Keywords: ALK inhibitor; Boron-containing compounds; In vivo efficacy; Lead compound.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Boron / pharmacology
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Lung Neoplasms* / drug therapy
  • Mice
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use

Substances

  • Anaplastic Lymphoma Kinase
  • Boron
  • Antineoplastic Agents
  • Protein Kinase Inhibitors