Development of highly selective, low-toxicity and orally available Mcl-1 inhibitors based on 3,5-dimethyl-4-sulfonimide-1H-pyrrole scaffold via P2/P3 dual pocket binding optimization

  • Eur J Med Chem. 2026 May 29:316:119010. doi: 10.1016/j.ejmech.2026.119010.
Junjie Wang  1 ,  Ke Xu  1 ,  Pengju Zhu  1 ,  Ziquan Zhao  1 ,  Shuai Wen  1 ,  Jinglong Zhao  1 ,  Yabin Xin  2 ,  Qidong You  3 ,  Zhengyu Jiang  4 ,  Mengchen Lu  5
Affiliations
  • 1. Jiang Su Key Laboratory of Drug Design and Optimization and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2. Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University Medical College, Suzhou, 215123, China.
  • 3. Jiang Su Key Laboratory of Drug Design and Optimization and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University Medical College, Suzhou, 215123, China. Electronic address: [email protected].
  • 4. Jiang Su Key Laboratory of Drug Design and Optimization and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 5. Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University Medical College, Suzhou, 215123, China. Electronic address: [email protected].
PMID: 42224935 DOI: 10.1016/j.ejmech.2026.119010
Abstract

Myeloid cell leukemia 1 (Mcl-1) is a pivotal anti-apoptotic protein, whose overexpression drives tumorigenesis, progression and drug resistance in multiple hematological malignancies. Herein, guided by a bioisosteric design, we replaced the sulfonyl group with a drug-like sulfonimide linker and synthesized a novel series of Mcl-1 inhibitors based on our previous lead compound DDO-8201. Among them, compound 52 displayed potent and selective Mcl-1 inhibition (Ki = 0.024 μM) with at least 400-fold selectivity over other Bcl-2 Family proteins. It showed an IC50 of 0.45 μM against Mcl-1-sensitive Molm-13 cells, superior to A1210477, and retained good activity against Venetoclax-resistant Molm-13 cells (Molm-13_VenR, IC50 = 1.16 μM). Moreover, 52 exhibited favorable drug-like properties, including good membrane permeability (Pe = 11.11 × 10-6 cm/s), water solubility (78.5 μg/mL), high stability (HLM, t1/2 = 1.83 h) and oral bioavailability (F% = 32%). This study provided a new strategy for Mcl-1 Inhibitor development, and 52 represents a promising candidate for overcoming Venetoclax resistance.

Keywords
Antitumor activity; Drug-likeness optimization; Mcl-1 inhibitors; Sulfonimide scaffold; Venetoclax-resistant.
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