2. Academic Validation
  3. Discovery and antitumor activity of Benzo[d]imidazol-containing 2,4-diarylaminopyrimidine analogues as ALK inhibitors with mutation-combating effects

Discovery and antitumor activity of Benzo[d]imidazol-containing 2,4-diarylaminopyrimidine analogues as ALK inhibitors with mutation-combating effects

  • Bioorg Med Chem. 2021 May 1:37:116108. doi: 10.1016/j.bmc.2021.116108.
Zheng Li 1,  Ming Guo 2,  Meng Cao 2,  Tianming Zhao 2,  Mingzhu Li 3,  Xin Zhai 4
Affiliations

Affiliations

  • 1 Department of Integrated Traditional Chinese and Western Medicine Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, China.
  • 2 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 Department of Integrated Traditional Chinese and Western Medicine Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, China. Electronic address: limingzhu198600@126.com.
  • 4 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: zhaixin_syphu@126.com.
PMID: 33756437 DOI: 10.1016/j.bmc.2021.116108
Abstract

To address drug resistance caused by ALK kinase mutations, a series of novel 2,4-diarylaminopyrimidine (DAAP) analogues were designed by incorporating 1H-benzo[d]imidazol motif onto the maternal framework. All compounds were efficiently synthesized and antiproliferative activities against Karpas299, H2228 and A549 cell lines were evaluated by MTT assay. Delightly, the most promising derivative H-11 was detected with IC50 values of 0.016 μM and 0.099 μM against ALK- positive Karpas299 and H2228 cells. Meanwhile, H-11 displayed encouraging enzymatic inhibitory potency with IC50 values of 2.7 nM, 3.8 nM and 5.7 nM toward ALKWT, ALKL1196M and ALKG1202R, respectively. Ultimately, the binding modes of optimal H-11 with ALK wild-type and mutants were ideally established which further confirmed the structural basis in accordance with the SARs analysis.

Keywords

2,4-Diarylaminopyrimidine; ALK; Antitumor evaluations; G1202R mutant; Synthesis.

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