Voruciclib is a selective orally administered CDK9 inhibitor with potential to treat both hematological malignancies and solid tumors.
Voruciclib, a selective orally administered, inhibitor of CDK9, is in clinical development for acute myeloid leukemia. Applications in solid tumors are also being evaluated in non-clinical models.
CDK9 has important functions in cell cycle regulation, including the modulation of two therapeutic targets in cancer: myeloid leukemia cell differentiation protein (“MCL1”) and the MYC proto-oncogene protein (“MYC”) which regulates cell proliferation and growth. Voruciclib is currently being evaluated in a Phase 1 trial evaluating dose and schedule in patients with relapsed or refractory (R/R) acute myeloid leukemia (“AML”). Applications in solid tumors are also being considered where MYC is dysregulated.
The CDK family of proteins are important cell cycle regulators responsible for the control of cell proliferation, differentiation, apoptosis, and DNA repair. CDK9, one of several members of the CDK family of proteins, functions as a gene transcription controller and is also involved in regulating protein degradation. Specifically, CDK9 is a promising target to treat a range of cancers because of its role in controlling two other proteins often dysregulated in cancerous cells: myeloid leukemia cell differentiation protein (“Mcl-1”) and the MYC proto-oncogene protein (“Myc”).
In pre-clinical studies voruciclib shows dose-dependent suppression of MCL1; in December 2017 a study of voruciclib published in the journal Nature Scientific Reports reported that the combination of voruciclib plus the BCL-2 inhibitor venetoclax was capable of inhibiting two master regulators of cell survival, MCL-1 and BCL-2, and achieved synergistic antitumor effect in an aggressive subset of DLBCL pre-clinical models. Additional preclinical studies demonstrate that the inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the BCL-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia. (Sig Transduct Target Ther 5, 17 (2020). https://doi.org/10.1038/s41392-020-0112-3.
The research suggests voruciclib’s potential as an attractive therapeutic target for treating cancers in combination with venetoclax or other BCL-2 inhibitors, to address potential resistance associated with MCL1, and is supportive of our ongoing clinical program evaluating voruciclib. Currently, we are evaluating voruciclib plus venetoclax in patients with R/R AML in a Phase 1 clinical trial. The trial started with the evaluation of dose and schedule of voruciclib as a monotherapy in patients with R/R B-cell malignancies and AML after failure of prior standard therapies to determine the safety, preliminary efficacy and maximum tolerated dose. The trial is now evaluating the dose and schedule of voruciclib in combination with venetoclax, a BCL2 inhibitor, to assess synergies and the opportunity for combination treatments, initially in patients with R/R AML.
Initial results from the Phase 1 study have demonstrated anti-leukemic activity across multiple heavily pretreated patients along with anticipated decreases in Mcl-1. No evidence of overlapping toxicity, and no dose limiting toxicities have been observed to date. Favorable pharmacokinetics have been observed, including a half-life supporting once-a-day oral dosing, dose proportional C-max and a high volume of distribution suggesting broad entry into tissues.
Dysregulation of MYC is associated with many cancers. CDK9 is a known regulator of MYC transcription and a modulator of MYC protein phosphorylation. Reported data in preclinical models demonstrates that voruciclib:
The research presented suggests that voruciclib could be an attractive therapeutic target for cancers driven by MYC overexpression such as those harboring KRAS mutations and warrants further investigation.
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