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

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.