Enhanced Oral Bioavailability of Alvocidib: The Development and Efficacy of TP-1287 Prodrug

Alvocidib, a CDK9 inhibitor, is known for its ability to trigger cancer cell apoptosis by reducing the levels of anti-apoptotic proteins like MCL-1. It is currently in Phase II trials for treating relapsed/refractory acute myeloid leukemia (AML) as part of a combination regimen with cytarabine and mitoxantrone. Alvocidib's potential extends beyond this regimen, particularly for cancers with high MCL-1 dependency, such as those of the breast, prostate, and lung. However, its clinical use is limited by its intravenous administration route.

The development of an oral form of alvocidib could enable chronic dosing to maintain MCL-1 suppression. Alvocidib's permeability and solubility at acidic pH present challenges for oral formulation. To address this, researchers synthesized a phosphate prodrug, TP-1287, which demonstrated improved solubility across a range of pH levels, including neutral and basic conditions.

Pharmacokinetic studies in mice showed that TP-1287 effectively converted to alvocidib, achieving high oral bioavailability. In tumor xenograft models, TP-1287 exhibited significant anti-tumor efficacy and a robust therapeutic dosing window, with substantial inhibition of the MCL-1 biomarker and tumor growth.

The prodrug TP-1287 overcomes solubility limitations of alvocidib and shows promising anti-tumor effects when orally administered. These findings support the progression of TP-1287 to clinical trials for solid tumors where MCL-1 suppression could be beneficial.

The research was presented by Wontak Kim and colleagues at the American Association for Cancer Research Annual Meeting in 2017.