Quantifying CDK inhibitor selectivity in live cells

Wells, Carrow; Vasta, James D.; Corona, Cesear; Wilkinson, Jennifer; Zimprich, Chad; Ingold, Morgan R.; Pickett, Julie E.; Drewry, David H.; Pugh, Kathryn M.; Schwinn, Marie K.; Hwang, Byounghoon; Zegzouti, Hicham; Huber, K.; Cong, Mei; Meisenheimer, Poncho; Willson, Timothy M.; Robers, Matthew B.

doi:10.1038/s41467-020-16559-0

Cited by 73 publications

(60 citation statements)

References 61 publications

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“…Abemaciclib has five-fold more potency for CDK4 than palbociclib or ribociclib ( 16 , 35 ). Unlike palbociclib and ribociclib, abemaciclib has been shown to have in-vivo inhibition of CDK1, CDK2, CDK5, CDK9, CDK14, CDKs16-18, GSK3α/β, CAMKIIγ/δ and PIM1 kinases ( 35 , 39 ). Abemaciclib is 10- to 100-fold less potent against CDK2 and CDK1 than CDK4/6 ( 40 ).…”

Section: Cell Cycle Dysregulationmentioning

confidence: 99%

Clinical and Pharmacologic Differences of CDK4/6 Inhibitors in Breast Cancer

et al. 2021

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Targeted therapies such as Cyclin Dependent Kinase 4 and 6 (CDK 4/6) inhibitors have improved the prognosis of metastatic hormone receptor (HR) positive breast cancer by combating the resistance seen with traditional endocrine therapy. The three approved agents currently in the market are palbociclib, ribociclib and abemaciclib. Besides the overall similarities associated with CDK4/6 inhibition, there are differences between the three approved agents that may explain the differences noted in unique clinical scenarios- monotherapy, patients with brain metastases or use in the adjuvant setting. This review article will explore the preclinical and pharmacological differences between the three agents and help understand the benefits seen with these agents in certain subgroups of patients with metastatic HR positive breast cancer.

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Section: Cell Cycle Dysregulationmentioning

confidence: 99%

Clinical and Pharmacologic Differences of CDK4/6 Inhibitors in Breast Cancer

et al. 2021

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“…16,17 Previously, cell TE for PRMT5 inhibitors has been demonstrated via imaging-based detection of symmetrically dimethylated nuclear proteins 45,46 as well as in a PRMT5-RIOK1 protein-protein interaction NanoBiT assay in permeabilised cells. 47,48 Recently, studies have shown that NanoBRET assays using bespoke ETP probes are a powerful means to study direct TE in a quantitative fashion 22,49 . While CETSA has been established for PRMT5 previously, 15 a key advantage of the NanoBRET system is its ability to provide a continuous quantitative readout of cellular TE.…”

Section: Discussionmentioning

confidence: 99%

A chemical biology toolbox to investigate in-cell target engagement and specificity of PRMT5-inhibitors

Rothweiler

Stefaniak

Ward

et al. 2022

Preprint

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Increasing evidence suggests the protein arginine methyltransferase PRMT5 as a contributor to tumorigenesis in various cancer types and several inhibitors have entered clinical trials. Robust assays to determine cellular target engagement and selectivity are an important asset for the optimisation of inhibitors and the design of relevant in vivo studies. Here we report a suite of chemical biology assays enabling quantitative assessment of PRMT5 inhibitor in-cell target engagement and global selectivity profiling using a representative set of inhibitors. With the help of a bespoke cellular probe, we assess inhibitor target occupancy in cells in relation to biochemical and functional cellular assays. Investigating the influence of SAM, the natural cofactor of PRMT5, our results support the hypothesis that SAM positively contributes to the engagement of substrate-competitive inhibitors via a PRMT5:SAM:inhibitor ternary complex. Extensive proteomic profiling studies by drug affinity chromatography and thermal profiling further indicate high specificity of the clinical PRMT5 inhibitor GSK3326595 (pemrametostat).

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“…For example, BMS-265246, which targets CDK1/2, was found to also be a potent CDK8/19 inhibitor. 108 Although probes have been widely used in kinase profiling, the development of chemical probe-free profiling methods might have advantages for expanding the target range, particularly non-kinase targets.…”

Section: Advances Of Property Evaluation Technologiesmentioning

confidence: 99%

An overview of kinase downregulators and recent advances in discovery approaches

Wang

et al. 2021

Sig Transduct Target Ther

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Since the clinical approval of imatinib, the discovery of protein kinase downregulators entered a prosperous age. However, challenges still exist in the discovery of kinase downregulator drugs, such as the high failure rate during development, side effects, and drug-resistance problems. With the progress made through multidisciplinary efforts, an increasing number of new approaches have been applied to solve the above problems during the discovery process of kinase downregulators. In terms of in vitro and in vivo drug evaluation, progress was also made in cellular and animal model platforms for better and more clinically relevant drug assessment. Here, we review the advances in drug design strategies, drug property evaluation technologies, and efficacy evaluation models and technologies. Finally, we discuss the challenges and perspectives in the development of kinase downregulator drugs.

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Quantifying CDK inhibitor selectivity in live cells

Cited by 73 publications

References 61 publications

Clinical and Pharmacologic Differences of CDK4/6 Inhibitors in Breast Cancer

Clinical and Pharmacologic Differences of CDK4/6 Inhibitors in Breast Cancer

A chemical biology toolbox to investigate in-cell target engagement and specificity of PRMT5-inhibitors

An overview of kinase downregulators and recent advances in discovery approaches

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