A patent and literature review of CDK12 inhibitors

Tang, Ruijun; Liu, Jing; Li, Shuyao; Zhang, Junjie; Yu, Chunhong; Liu, Honglu; Chen, Fang; Lv, Lu; Zhang, Qian; Yuan, Kai; Shao, Hao

doi:10.1080/13543776.2022.2126765

Cited by 5 publications

(14 citation statements)

References 51 publications

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“…In Drosophila and human cells, CDK12 is involved in transcription elongation and can phosphorylate the RNA pol II CTD serine at the second position [10]. Certain enzymes, namely those needed for DNA damage response (DDR), DNA synthesis, and restoration, are transcriptionally elongated by CDK12 [11]. The pre-mRNA polyadenylation, cleavage, and splicing processes are also carried out by CDK12 [11].…”

Section: Summary Of Cdk12 Inhibitorsmentioning

confidence: 99%

Efficacy and mechanism of cyclin-dependent kinase inhibitors against cancer

Pei

2023

TNS

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This paper focuses on an overview of the development progress of different cyclin-dependent kinase (CDK) inhibitors. The CDKS are a group of kinases that are indispensable in the cell cycle. However, when it comes to cancer, the cell cycle is not healthy which causes malignancy of the cell that is able to mitosis infinitely. Considering the CDK are a group of molecules that is fundament during mitosis, researchers have developed its inhibitors to inhibit the effect that it has during the cell cycle to postpone the growth of cancer and lead to cancer cell apoptosis. This paper targets on the CDK inhibitors of pan-CDK, CDK4/6, 7, 9, and 12, also introducing their development history and current stages in clinical trials, as well as the drugs related to these CDK inhibitors that are FDA-approved for cancer treatment. In addition, the paper also introduces the future potentials of CDK inhibitors in the treatment and therapy of cancer-related diseases.

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Section: Summary Of Cdk12 Inhibitorsmentioning

confidence: 99%

Efficacy and mechanism of cyclin-dependent kinase inhibitors against cancer

Pei

2023

TNS

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“…11 Aberrant expression of CDK12 leads to disruption of cellular metabolism and promotes cancer production and progression. 12–14 Knockdown of the CDK12 gene inhibited the growth and proliferation of A2780 ovarian cancer cells and induced apoptosis of cancer cells. 15 Currently, the traditional small-molecule inhibitors of CDK12 mainly include pan-inhibitors, PROTAC degraders and molecular glue degraders.…”

Section: Introductionmentioning

confidence: 99%

Research progress of anticancer drugs targeting CDK12

Yan

Zhang

et al. 2023

RSC Med. Chem.

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“…9−11 These inhibitors have shown certain efficacy in cancer treatment models but have not been put into clinical usage mainly because of their drug resistance or poor pharmacokinetics. 12 Moreover, only a small fraction of the static structures of CDK12/CDK13-inhibitor complexes have been characterized by X-ray diffraction. 9,11,13,14 The dynamic conformations of CDK12/CDK13-CycK complexes modulated by inhibitors are difficult to be captured by conventional structural biology tools.…”

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confidence: 99%

“…The overall profiles of CDK12/CDK13 lysine reactivities were similar when binding with different inhibitors, which indicates these inhibitors share a similar inhibition molecular mechanism. However, although the kinase domains of CDK12 and CDK13 are highly conserved, 12 distinct profiles of lysine reactivities were observed because of their different structures. 14,25 Part of the lysine residues showed decreasing reactivities after inhibitor combination, which was attributed to the stabilization effects of inhibitors on their local structures via the enhanced proximal noncovalent interactions.…”

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confidence: 99%

“…To date, the known small molecule inhibitors of CDK12/CDK13 are all ATP-competitive inhibitors developed through structural optimization of lead compounds, high-throughput screening, and structure–activity relationship (SAR) study. − These inhibitors have shown certain efficacy in cancer treatment models but have not been put into clinical usage mainly because of their drug resistance or poor pharmacokinetics . Moreover, only a small fraction of the static structures of CDK12/CDK13-inhibitor complexes have been characterized by X-ray diffraction. ,,, The dynamic conformations of CDK12/CDK13-CycK complexes modulated by inhibitors are difficult to be captured by conventional structural biology tools.…”

mentioning

confidence: 99%

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

Bai

Zhao

et al. 2023

J. Am. Chem. Soc.

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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 molecular interactions and overall protein assembly of CDK12/CDK13-cyclin K (CycK) complexes under the modulation of small molecule inhibitors. The essential structure insights, including inhibitor binding pocket, binding strength, interfacial molecular 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 molecular level.

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A patent and literature review of CDK12 inhibitors

Cited by 5 publications

References 51 publications

Efficacy and mechanism of cyclin-dependent kinase inhibitors against cancer

Efficacy and mechanism of cyclin-dependent kinase inhibitors against cancer

Research progress of anticancer drugs targeting CDK12

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

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