TP-1287 (Oral CDK9 Inhibitor)

Rationale

Alvocidib is currently delivered by intravenous infusion in ongoing investigational studies.1 TP-1287 is a prodrug of alvocidib with significantly enhanced solubility under neutral and basic conditions and has shown improved oral bioavailability in preclinical models. The promoiety of the prodrug is enzymatically cleaved, yielding the parent drug, alvocidib, a potent inhibitor of CDK9.2

Preclinical Activity

TP-1287, delivered orally in preclinical models, has shown significant activity in downregulating transcription of target genes of CDK9, such as MCL1. The consequent downregulation of MCL-1 protein expression is correlated to tumor regression.2

Clinical Opportunities

The oral delivery of alvocidib, in the form of TP-1287, opens new opportunities for the development of the alvocidib franchise. The oral administration of TP-1287 may allow for chronic dosing of alvocidib, which may lead to a complete and durable inhibition of CDK9. This may be important for its development in disease settings where oral administration is preferred or in using TP-1287 in combination with other targeted agents. TP-1287 builds on the robust clinical dataset of alvocidib, yet will allow for the exploration of an oral dosing route.2

TP-1287 is an investigational agent and is not approved by the US FDA or any other regulatory authorities.

References: 1. Zeidner JF, Foster MC, Blackford AL, et al. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015;100(9):1172-1179. 2. Kim W, Haws H, Peterson P, et al. TP-1287, an oral prodrug of the cyclin-dependent kinase-9 inhibitor alvocidib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 suppl):Abstract nr 5133.


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