A Modular, Multi-Part, Multi-Arm, Phase 1/2 Study to Evaluate the Safety and Tolerability of CT7439 Alone and in Combination with Anticancer Treatments in Participants with Solid Malignancies

This modular, multi-part, multi-arm, Phase 1/2, FIH study allows the evaluation of the safety and tolerability of CT7439, dosed as a monotherapy and in combination with anticancer treatment in participants with solid malignancies.

Start Date16 Aug 2024

Sponsor / Collaborator

Carrick Therapeutics Ltd.Startup

100 Clinical Results associated with CDK13 x CDK12 x CCNK

100 Translational Medicine associated with CDK13 x CDK12 x CCNK

0 Patents (Medical) associated with CDK13 x CDK12 x CCNK

Literatures (Medical) associated with CDK13 x CDK12 x CCNK

01 Jan 2024·Journal of Biological Chemistry

The reversible inhibitor SR-4835 binds Cdk12/cyclin K in a noncanonical G-loop conformation

Article

Author: Schmitz, Maximilian ; Geyer, Matthias ; Anand, Kanchan ; Roush, William R ; Moecking, Jonas ; Düster, Robert ; Duckett, Derek R ; Monastyrskyi, Andrii ; Kaltheuner, Ines H

Inhibition of cyclin-dependent kinases (CDKs) has evolved as an emerging anticancer strategy. In addition to the cell cycle-regulating CDKs, the transcriptional kinases Cdk12 and Cdk13 have become the focus of interest as they mediate a variety of functions, including the transition from transcription initiation to elongation and termination, precursor mRNA splicing, and intronic polyadenylation. Here, we determine the crystal structure of the small molecular inhibitor SR-4835 bound to the Cdk12/cyclin K complex at 2.68 Å resolution. The compound's benzimidazole moiety is embedded in a unique hydrogen bond network mediated by the kinase hinge region with flanking hydroxy groups of the Y815 and D819 side chains. Whereas the SR-4835 head group targets the adenine-binding pocket, the kinase's glycine-rich loop is shifted down toward the activation loop. Additionally, the αC-helix adopts an inward conformation, and the phosphorylated T-loop threonine interacts with all three canonical arginines, a hallmark of CDK activation that is altered in Cdk12 and Cdk13. Dose-response inhibition measurements with recombinant CMGC kinases show that SR-4835 is highly specific for Cdk12 and Cdk13 following a 10-fold lower potency for Cdk10. Whereas other CDK-targeting compounds exhibit tighter binding affinities and higher potencies for kinase inhibition, SR-4835 can be considered a selective transcription elongation antagonist. Our results provide the basis for a rational improvement of SR-4835 toward Cdk12 inhibition and a gain in selectivity over other transcription regulating CDKs.

31 May 2023·Journal of the American Chemical Society

Structural Mass Spectrometry Probes the Inhibitor-Induced Allosteric Activation of CDK12/CDK13-Cyclin K Dissociation

Article

Author: Chen, Kaixian ; Lai, Can ; Liu, Zheyi ; Zhao, Shan ; Zhao, Heng ; Li, Yuanqing ; Bai, Yu ; Luo, Cheng ; Yang, Xueming ; Wang, Fangjun

The rational design and development of effective inhibitors for cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) are largely dependent on the understanding of the dynamic inhibition conformations but are difficult to be achieved by conventional characterization tools.Herein, we integrate the structural mass spectrometry (MS) methods of lysine reactivity profiling (LRP) and native MS (nMS) to systematically interrogate both the dynamic mol. interactions and overall protein assembly of CDK12/CDK13-cyclin K (CycK) complexes under the modulation of small mol. inhibitors.The essential structure insights, including inhibitor binding pocket, binding strength, interfacial mol. details, and dynamic conformation changes, can be derived from the complementary results of LRP and nMS.We find the inhibitor SR-4835 binding can greatly destabilize the CDK12/CDK13-CycK interactions in an unusual allosteric activation way, thereby providing a novel alternative for the kinase activity inhibition.Our results underscore the great potential of LRP combination with nMS for the evaluation and rational design of effective kinase inhibitors at the mol. level.

01 Jan 2022·European Journal of Medicinal Chemistry

Noncovalent CDK12/13 dual inhibitors-based PROTACs degrade CDK12-Cyclin K complex and induce synthetic lethality with PARP inhibitor

Article

Author: Yang, Bo ; Li, Kailin ; Hong, Ju ; Zhu, Cheng-Liang ; Zhou, Zhesheng ; Chen, Xuankun ; Niu, Tian ; He, Qiaojun ; Dong, Xiaowu ; Cao, Ji ; Jiang, Li

Cyclin-dependent kinase 12 (CDK12) plays a crucial role in DNA-damage response gene transcription and has recently been validated as a promising target in cancer therapy. However, existing CDK12 inhibitors potently inhibit its closest isoform CDK13, which could cause potential toxicity. Therefore, the development of CDK12 inhibitors with isoform-selectivity against CDK13 continues to be a challenge. By taking advantage of the emerging PROteolysis-TArgeting Chimeras (PROTACs) approach, we have synthesized a potent PROTAC degrader PP-C8 based on the noncovalent dual inhibitors of CDK12/13 and demonstrated its specificity for CDK12 over CDK13. Notably, PP-C8 induces profound degradation of cyclin K simultaneously and downregulates the mRNA level of DNA-damage response genes. Global proteomics profiling revealed PP-C8 is highly selective toward CDK12-cyclin K complex. Importantly, PP-C8 demonstrates profound synergistic antiproliferative effects with PARP inhibitor in triple-negative breast cancer (TNBC). The potent and selective CDK12 PROTAC degrader developed in this study could potentially be used to treat CDK12-dependent cancers as combination therapy.

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