VIP152 is a selective CDK9 inhibitor with pre-clinical in vitro and in vivo efficacy in chronic lymphocytic leukemia.

Autor: Sher S; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Whipp E; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Walker J; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Zhang P; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Beaver L; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Williams K; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Orwick S; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Ravikrishnan J; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Walker B; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Perry E; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Gregory C; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Purcell M; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Pan A; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Yan P; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Alinari L; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Johnson AJ; Vincerx Pharma, Palo Alto, CA, USA., Frigault MM; Vincerx Pharma, Palo Alto, CA, USA., Greer JM; Vincerx Pharma, Palo Alto, CA, USA., Hamdy A; Vincerx Pharma, Palo Alto, CA, USA., Izumi R; Vincerx Pharma, Palo Alto, CA, USA., Mo X; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Sampath D; Department of Hematopoietic Biology & Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Woyach J; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Blachly J; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA., Byrd JC; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA. byrd2jc@ucmail.uc.edu., Lapalombella R; Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA. rosa.lapalombella@osumc.edu.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2023 Feb; Vol. 37 (2), pp. 326-338. Date of Electronic Publication: 2022 Nov 14.
DOI: 10.1038/s41375-022-01758-z
Abstrakt: Chronic lymphocytic leukemia (CLL) is effectively treated with targeted therapies including Bruton tyrosine kinase inhibitors and BCL2 antagonists. When these become ineffective, treatment options are limited. Positive transcription elongation factor complex (P-TEFb), a heterodimeric protein complex composed of cyclin dependent kinase 9 (CDK9) and cyclin T1, functions to regulate short half-life transcripts by phosphorylation of RNA Polymerase II (POLII). These transcripts are frequently dysregulated in hematologic malignancies; however, therapies targeting inhibition of P-TEFb have not yet achieved approval for cancer treatment. VIP152 kinome profiling revealed CDK9 as the main enzyme inhibited at 100 nM, with over a 10-fold increase in potency compared with other inhibitors currently in development for this target. VIP152 induced cell death in CLL cell lines and primary patient samples. Transcriptome analysis revealed inhibition of RNA degradation through the AU-Rich Element (ARE) dysregulation. Mechanistically, VIP152 inhibits the assembly of P-TEFb onto the transcription machinery and disturbs binding partners. Finally, immune competent mice engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with VIP152 demonstrated reduced disease burden and improvement in overall survival compared to vehicle-treated mice. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.
(© 2022. The Author(s).)
Databáze: MEDLINE
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