2. Academic Validation
  3. A new cyclin-dependent kinase-9 inhibitor A09-003 induces apoptosis in acute myeloid leukemia cells with reduction of myeloid cell leukemia sequence-1 protein

A new cyclin-dependent kinase-9 inhibitor A09-003 induces apoptosis in acute myeloid leukemia cells with reduction of myeloid cell leukemia sequence-1 protein

  • Chem Biol Interact. 2023 Sep 1:382:110554. doi: 10.1016/j.cbi.2023.110554.
Kyoung Mi Sim 1,  So Young Kim 1,  Supyong Hwang 2,  Sojung Park 2,  Bo Ra Lee 2,  Kyyoub Nam 3,  SeakHee Oh 4,  Inki Kim 5
Affiliations

Affiliations

  • 1 Biomedical Research Center, ASAN Institute for Life Sciences, ASAN Medical Center, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, Republic of Korea.
  • 2 Convergence Medicine Research Center (CREDIT), ASAN Institute for Life Sciences, ASAN Medical Center, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, Republic of Korea.
  • 3 Pharos-I BIO, Seoul, Republic of Korea.
  • 4 Department of Pediatrics, Asan Medical Center Children's Hospital, University Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
  • 5 Biomedical Research Center, ASAN Institute for Life Sciences, ASAN Medical Center, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, Republic of Korea; Convergence Medicine Research Center (CREDIT), ASAN Institute for Life Sciences, ASAN Medical Center, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, Republic of Korea; Department of Pharmacology, University of Ulsan College of Medicine, 88 Olympicro 43 gil, Songpa-Gu, Seoul, Republic of Korea. Electronic address: ik.kim@amc.seoul.kr.
PMID: 37271215 DOI: 10.1016/j.cbi.2023.110554
Abstract

Acute myeloid leukemia (AML) is the most common type of hematological disease in adults, and has a very poor outcome [1]. Based on its wide range of efficacy in AML models, a small-molecule inhibitor of the anti-apoptotic protein Bcl-2, venetoclax (ABT-199/GDC-0199), was developed for clinical trials. However, venetoclax showed limited monotherapy activity [2]. The overexpression of myeloid cell leukemia sequence-1 protein (Mcl-1)-due to mutations in Fms-like tyrosine kinase 3 internal tandem duplication (Flt-3 ITD)-was considered to be the main reason for low efficacy of venetoclax in clinical trials [3-5]. To achieve venetoclax sensitization in AML, targeting CDK-9 with venetoclax is a promising therapeutic strategy. In this study, we developed A09-003 as a potent inhibitor of CDK-9, with an IC50 value of 16 nM. A09-003 inhibited cell proliferation in various leukemia cell lines. In particular, the proliferation inhibitory effect of A09-003 was most potent in MV4-11 and Molm-14 cells, harboring the Flt-3 ITD mutation with a high expression profile of Mcl-1. Marker analysis revealed that A09-003 reduced CDK-9 phosphorylation and reduced RNA polymerase II activity with decreased Mcl-1 expression. Finally, combining A09-003 with venetoclax induced apoptotic cell death in a synergistic manner. In summary, this study shows the potential of A09-003 in AML therapy.

Keywords

A09-003; AML; CDK9; Mcl-1.

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