Rational Design of a Potent, Selective, and Metabolically Stable CDK9 Inhibitor to Counteract Osimertinib Resistance through Mcl-1 Suppression and Enhanced BRD4 Co-Targeting

  • J Med Chem. 2025 Feb 27;68(4):4929-4950. doi: 10.1021/acs.jmedchem.4c03168.
Tizhi Wu  1 ,  Jiali Huang  1 ,  Xiankang Zhang  1 ,  Feihai Ma  1 ,  Shijing Yu  1 ,  Yifang Liu  1 ,  Yifan Xu  1 ,  Shiqi Wu  1 ,  Alexander V Finko  2 ,  Zhiyu Li  1 ,  Li Feng  3 ,  Jinlei Bian  1
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
  • 2. Department of Chemistry, Lomonosov Moscow State University (MSU), Moscow 119991, Russia.
  • 3. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, PR China.
PMID: 39947929 DOI: 10.1021/acs.jmedchem.4c03168
Abstract

Overcoming osimertinib resistance in NSCLC treatment remains a significant clinical challenge. CDK9 has emerged as a promising target due to its critical role in sustaining oncogenic transcriptional programs, particularly via Mcl-1 regulation. Herein, we report the structure-guided optimization of a previously identified CDK9 Inhibitor (Z11), resulting in the discovery of T7, a potent, selective, and metabolically stable candidate (IC50 = 1.2 nM). T7 effectively suppressed cell proliferation, reduced colony formation, and induced Apoptosis in Osimertinib-resistant NSCLC cells by downregulating Mcl-1. Furthermore, T7 significantly inhibited the growth of resistant organoids and demonstrated marked antitumor efficacy in a xenograft model. Notably, combining T7 with the BRD4 Inhibitor JQ1 further enhanced antitumor activity both in vitro and in vivo, revealing a complementary therapeutic strategy. These findings identify T7 as a promising next-generation CDK9 Inhibitor for addressing Osimertinib resistance in NSCLC and underscore the potential of transcriptional cotargeting approaches to improve clinical outcomes.

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