Innovative CDK9 Inhibitor Shows Promise in Combating Drug Resistance in Blood Cancers

A research team has developed a novel class of compounds targeting CDK9, a key enzyme involved in cancer cell transcription. These compounds can effectively inhibit both the wild-type form of CDK9 and its mutant variants associated with drug resistance, offering new hope for treating hematological malignancies. The breakthrough was detailed in the Journal of Medicinal Chemistry, highlighting the significance of this discovery in overcoming resistance mechanisms.

Hematological cancers, such as leukemia and lymphoma, often exhibit high morbidity and mortality rates. CDK9, a serine/threonine kinase, plays a critical role in controlling gene transcription, making it a prime target for therapeutic interventions. However, resistance to existing CDK9 inhibitors, especially due to the L156F mutation in the kinase domain—also a common single nucleotide polymorphism—has limited clinical success.

To tackle this challenge, researchers led by Prof. Liu Qingsong and Prof. Liu Jing at the Hefei Institutes of Physical Science employed high-throughput screening coupled with computer-aided drug design. They synthesized and optimized a series of dihydroisoquinolinone derivatives, ultimately identifying IHMT-CDK9-24 as the most potent candidate. This compound demonstrated remarkable inhibitory activity, with IC₅₀ values of 1.2 nM against wild-type CDK9 and 3.3 nM against the L156F mutant.

Mechanistic studies revealed that IHMT-CDK9-24 suppresses downstream targets such as phosphorylated RNA Pol II (Ser2), c-MYC, and MCL-1, leading to apoptosis in hematologic cancer cells. It also exhibits high selectivity for CDK9 over other CDKs and effectively inhibits proliferation across various blood cancer cell lines. In vivo experiments confirmed its strong antitumor effects in mouse models, where the compound effectively shut down cancer cell survival signals.

According to Prof. Liu Jing, the compound 'works by shutting down the survival signals of cancer cells, essentially turning off their life support system and triggering self-destruction.' These promising preclinical results suggest that IHMT-CDK9-24 could serve as a foundation for developing effective therapies to counteract drug resistance in hematological malignancies, offering new clinical strategies for these challenging cancers.

This innovative study not only introduces a potent candidate drug but also advances the understanding of overcoming kinase mutation-induced resistance, marking a significant step forward in targeted cancer therapy.

Source: https://medicalxpress.com/news/2025-05-potent-cdk9-inhibitor-drug-resistance.html