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

Abstract

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.

Targeting CDK9 with selective inhibitors or degraders in tumor therapy: an overview of recent developments

“… 106 VIP152 binding to P-TEFb leads to its dissociation from the 7SK snRNP complex and inhibits P-TEFb binding to RNAP II, resulting in the loss of proliferative signaling and MCL-1 expression. 128 …”

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications

“…Overall, 13 achieves better inhibitory efficacy than 27 , and it is one of the most potent inhibitors currently . With its outstanding performance, 13 has entered multiple clinical trials (NCT02635672). , …”

“…81 With its outstanding performance, 13 has entered multiple clinical trials (NCT02635672). 58,82 AZ5576 ( 28) is another pyridine-based selective inhibitor with notable inhibitory effect on CDK9 and demonstrates effective control over diffuse large B-cell lymphoma in vitro (Figure 6D). 83 On the base of 28, introducing halogen at C4 of pyridine to enhance potency and solubility and introducing dimethylsubstituted pyrrolidines at C5 to attain better interaction with P-loop, researchers get a more potent inhibitor 8 (Figure 6B).…”

Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation

“…While the remaining 20% form complexes with Cyclin T2A, Cyclin T2B, or Cyclin K. CDK9 expression has been found to be dysregulated in various types of cancer. − Inhibition of CDK9 results in transient transcriptional suppression and preferential depletion of apoptosis-related proteins with short half-lives, such as Mcl-1, c-Myc, and XIAP. So far, several selective CDK9 inhibitors have entered clinical research successively for the treatment of malignant hematological tumors such as acute myeloid leukemia (AML), including AZD4573, VIP152, KB-0742, et al (Figure ), and most of the design concepts of CDK9 inhibitors are focused on CDK subtype selectivity and properties suitable for achieving short target engagement. , Recent studies have shown that MYC gene mutations and abnormal Mcl-1 expression are also one of the main factors driving the onset and metastasis of CRC in addition to malignant hematological tumors. − Therefore, targeting CDK9 might work as an appealing strategy for treating CRC. In this work, we preliminarily demonstrated the feasibility of CDK9 as a potent target of treatment for colorectal cancer, and a novel CDK9 inhibitor, named CLZX-205, was designed and synthesized, which possessed acceptable pharmacokinetic properties and antitumor efficacy in vitro and in vivo.…”

“…11−14 Inhibition of CDK9 results in transient transcriptional suppression and preferential depletion of apoptosis-related proteins with short half-lives, such as Mcl-1, c-Myc, and XIAP. So far, several selective CDK9 inhibitors have entered clinical research successively for the treatment of malignant hematological tumors such as acute myeloid leukemia (AML), including AZD4573, 15 VIP152, 16 KB-0742, 17 et al (Figure 1), and most of the design concepts of CDK9 inhibitors are focused on CDK subtype selectivity and properties suitable for achieving short target engagement. 15,16 Recent studies have shown that MYC gene mutations and abnormal Mcl-1 expression are also one of the main factors driving the onset and metastasis of CRC in addition to malignant hematological tumors.…”