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.

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.