HMN 2025: How Potent CDK9 inhibitor reveals promise for overcoming drug resistance in hematological malignancies

A analysis group has developed a brand new class of compounds that successfully inhibit each wild-type CDK9 and its drug-resistant mutant type, providing a promising technique for treating hematological malignancies.

The findings have been revealed within the Journal of Medicinal Chemistry.

Hematological malignancies are cancers with excessive morbidity and mortality. CDK9, a serine/threonine kinase concerned in transcription regulation, is taken into account a key therapeutic goal.

However, resistance to CDK9 inhibitors—notably because of the L156F mutation within the kinase area—could pose a problem for future scientific analysis. And this mutation, additionally a recognized single nucleotide polymorphism (SNP) web site, represents a possible widespread mechanism of resistance.

To tackle this problem, the researchers, led by Prof. Liu Qingsong and Prof. Liu Jing from the Hefei Institutes of Physical Science of the Chinese Academy of Sciences, used high-throughput screening to determine a lead compound with CDK9 inhibitory exercise.

Guided by computer-aided drug design and structure-activity relationship evaluation, they synthesized and optimized a collection of dihydroisoquinolinone derivatives. Among them, IHMT-CDK9-24 emerged as probably the most promising candidate compound.

IHMT-CDK9-24 demonstrated potent inhibitory exercise towards each wild-type CDK9 (IC₅₀ = 1.2 nM) and the L156F mutant (IC₅₀ = 3.3 nM).

Mechanistic research revealed that it suppressed key downstream targets comparable to phosphorylated RNA Pol II (Ser2), c-MYC, and MCL-1, finally inducing apoptosis in hematologic cancer cells. The compound additionally confirmed excessive selectivity for CDK9 over different cyclin-dependent kinases (CDKs) and successfully inhibited the proliferation of assorted hematological cancer cell strains.

“It works by shutting down the survival alerts of cancer cells,” stated Prof. Liu Jing. “It’s like turning off their life help system and triggering them to self-destruct.”

In vivo pharmacodynamic research additional confirmed the compound’s sturdy antitumor efficacy in mouse models bearing hematologic malignancies with totally different genetic backgrounds.

According to the researchers, this study not solely presents a promising candidate drug but in addition a novel therapeutic technique for overcoming drug resistance in CDK9-targeted cancer remedy.