Our Research

Alvocidib (CDK9 Inhibitor)

Alvocidib is an investigational, intravenously administered, small molecule cyclin-dependent kinase 9 (CDK9) inhibitor.1

Mechanism of Action

Alvocidib is a potent inhibitor of CDK9.2 The primary function of CDK9 is to activate transcription elongation by phosphorylating the C-terminal domain of RNA polymerase II.3 By inhibiting CDK9, alvocidib downregulates the transcription of target genes, including the myeloid cell leukemia-1 (MCL-1) gene.In MCL-1—dependent acute myeloid leukemia (AML), downregulation of MCL-1 protein expression can trigger apoptosis of leukemic blasts.4

In MCL-1—dependent acute myeloid leukemia (AML), downregulation of MCL-1 protein expression can trigger apoptosis of leukemic blasts. (superscript 4)

Clinical Development

Alvocidib has shown clinical activity in multiple types of solid tumors and hematologic malignancies.2 Tolero’s initial focus is the development of alvocidib in MCL-1–dependent AML.

Proof of concept was shown in a multicenter, randomized, phase 2 clinical trial, in which alvocidib in combination with cytarabine and mitoxantrone (ACM) was compared to the standard-of-care cytarabine/daunorubicin (7+3) regimen in newly diagnosed, intermediate- and high-risk AML patients. ACM showed a significant improvement in the complete remission (CR) rate compared to 7+3.5

Alvocidib is an investigational, intravenously administered, small molecule cyclin-dependent kinase 9 (CDK9) inhibitor not yet approved by the US FDA or any other health authorities.


    References:
  1. Yeh YY, Chen R, Hessler J, et al. Up-regulation of CDK9 kinase activity and Mcl-1 stability contributes to the acquired resistance to cyclin-dependent kinase inhibitors in leukemia. Oncotarget. 2015;6(5):2667-2679.
  2. Morales F, Giordano A. Overview of CDK9 as a target in cancer research. Cell Cycle. 2016;15(4):519-527.
  3. Ocana A, Pandiella A. Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies. Oncotarget. 2017;8(13):22218-22234.
  4. Thomas D, Powell JA, Vergez F, et al. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood. 2013;122(5):738-748.
  5. 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.
  6. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419-425.