An exciting new research paper has been published in Oncotargets Volume 14 on December 20, 2023, titled „The Pharmacodynamic and Mechanistic Basis of the Antineoplastic Effects of GFH009, an Effective and Highly Selective CDK9 Inhibitor for the Treatment of Hematologic Malignancies.“
To evade cell cycle controls, malignant cells rely on fast expression of selected proteins to attenuate proapoptotic signals resulting from damage caused by both cancer treatments and uncontrolled over-proliferation. The signal transduction dependent on Cyclin-dependent kinase 9 (CDK9) induces the transcription of downstream oncogenes and promotes tumor growth, especially in hyperproliferative „oncogene addicted“ cancer types such as human hematologic malignancies (HHMs). In this new study, researchers Fusheng Zhou, Lili Tang, Siyuan Le, Mei Ge, Dragan Cicic, Fubo Xie, Jinmin Ren, Jiong Lan, and Qiang Lu from GenFleet Therapeutics Inc. and Sellas Life Sciences Group aimed to summarize the current knowledge of the mode of action (MOA) of GFH009 and explain its robust anticancer activity.
„Understanding the MOA of GFH009 enables a more optimal clinical development path, as there is the potential for significant benefits in patients with hematologic malignancies.“
GFH009, an effective, highly selective CDK9 inhibitor small molecule, exhibited antiproliferative activity in various HHM-derived cell lines and induced apoptosis at IC50 values below 0.2 μM in 7/10 tested lines. GFH009 inhibited tumor growth at all doses compared to controls and induced dose-dependent apoptosis.
Bi-weekly injections of 10 mg/kg of GFH009 Maleate significantly prolonged the survival of MV-4-11 xenograft-bearing rodents, while their body weight remained stable. After drug exposure, there was a significant reduction in MCL-1 and c-MYC protein expression in vitro and in vivo. By the rapid „on-off“ inhibition of CDK9, GFH009 exerts a proapoptotic effect on preclinical HHM models triggered by the dynamic withdrawal of critical cell survival signals.
„Our findings mechanistically demonstrate that CDK9 is a vulnerable target in various HHMs, and together with the previously demonstrated superior kinome selectivity of GFH009 compared to other CDK9 inhibitors, they strongly support the rationale for ongoing clinical trials with this drug in acute myeloid leukemia and other HHMs.“
Zhou, F., et al. (2023). The Pharmacodynamic and Mechanistic Basis of the Antineoplastic Effects of GFH009, an Effective and Highly Selective CDK9 Inhibitor for the Treatment of Hematologic Malignancies. Oncotarget. doi.org/10.18632/oncotarget.28543.