Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion

Qiu, Xiaqiu; Li, Yuanqing; Yu, Bin; Ren, Jie; Huang, Hua; Wang, Min; Ding, Hong; Li, Zhiyu; Wang, Jubo; Bian, Jinlei

doi:10.1016/j.ejmech.2020.113091

Cited by 59 publications

(47 citation statements)

References 40 publications

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“…This allows the PROTAC to ensure ubiquitination of the target protein and initiate degradation. The protein targeting domain can be a small molecule, mimicking a known inhibitor of the target protein ( Qiu et al, 2021 ; Yan et al, 2021 ) or a peptide sequence, designed based on POI crystal structure and the known protein-protein interaction motifs ( Jiang et al, 2018 ; Jin et al, 2020 ).…”

Section: Main Bodymentioning

confidence: 99%

Molecular Strategies to Target Protein Aggregation in Huntington’s Disease

Jarosińska

Rüdiger

2021

Front. Mol. Biosci.

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Huntington’s disease (HD) is a neurodegenerative disorder caused by the aggregation of the mutant huntingtin (mHTT) protein in nerve cells. mHTT self-aggregates to form soluble oligomers and insoluble fibrils, which interfere in a number of key cellular functions. This leads to cell quiescence and ultimately cell death. There are currently still no treatments available for HD, but approaches targeting the HTT levels offer systematic, mechanism-driven routes towards curing HD and other neurodegenerative diseases. This review summarizes the current state of knowledge of the mRNA targeting approaches such as antisense oligonucleotides and RNAi system; and the novel methods targeting mHTT and aggregates for degradation via the ubiquitin proteasome or the autophagy-lysosomal systems. These methods include the proteolysis-targeting chimera, Trim-Away, autophagosome-tethering compound, autophagy-targeting chimera, lysosome-targeting chimera and approach targeting mHTT for chaperone-mediated autophagy. These molecular strategies provide a knowledge-based approach to target HD and other neurodegenerative diseases at the origin.

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Section: Main Bodymentioning

confidence: 99%

Molecular Strategies to Target Protein Aggregation in Huntington’s Disease

Jarosińska

Rüdiger

2021

Front. Mol. Biosci.

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“…The most potent compound, B03 ( 31 , Figure 7 ), inhibited cell growth much more effectively than BAY-1143572 alone, with no evident inhibition of other kinases. Moreover, it could induce CDK9 degradation in vivo ( Qiu et al, 2021 ).…”

Section: Recent Progress Of Protacs Targeting Protein Kinasementioning

confidence: 99%

Targeting Protein Kinases Degradation by PROTACs

Cai

Shao

et al. 2021

Front. Chem.

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Kinase dysregulation is greatly associated with cell proliferation, migration and survival, indicating the importance of kinases as therapeutic targets for anticancer drug development. However, traditional kinase inhibitors binding to catalytic or allosteric sites are associated with significant challenges. The emergence of resistance and targeting difficult-to-degrade and multi-domain proteins are significant limiting factors affecting the efficacy of targeted anticancer drugs. The next-generation treatment approaches seem to have overcome these concerns, and the use of proteolysis targeting chimera (PROTAC) technology is one such method. PROTACs bind to proteins of interest and recruit E3 ligase for degrading the whole target protein via the ubiquitin-proteasome pathway. This review provides a detailed summary of the most recent signs of progress in PROTACs targeting different kinases, primarily focusing on new chemical entities in medicinal chemistry.

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“…PROTACs have also been designed to inhibit other CDKs. Qiu et al designed a series of PROTACs based on CDK9 inhibitor atuveciclib (BAY-1143572) and showed anti-leukemic effects at low nanomolar concentrations, also in vivo [128].…”

Section: Dual Kinase Inhibitors and Novel Approachesmentioning

confidence: 99%

Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-)Clinical Application and Promising Approaches

Richter

Schoenwaelder

Sender

et al. 2021

Cancers

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Genetically altered stem or progenitor cells feature gross chromosomal abnormalities, inducing modified ability of self-renewal and abnormal hematopoiesis. Cyclin-dependent kinases (CDK) regulate cell cycle progression, transcription, DNA repair and are aberrantly expressed in hematopoietic malignancies. Incorporation of CDK inhibitors (CDKIs) into the existing therapeutic regimens therefore constitutes a promising strategy. However, the complex molecular heterogeneity and different clinical presentation is challenging for selecting the right target and defining the ideal combination to mediate long-term disease control. Preclinical and early clinical data suggest that specific CDKIs have activity in selected patients, dependent on the existing rearrangements and mutations, potentially acting as biomarkers. Indeed, CDK6, expressed in hematopoietic cells, is a direct target of MLL fusion proteins often observed in acute leukemia and thus contributes to leukemogenesis. The high frequency of aberrancies in the retinoblastoma pathway additionally warrants application of CDKIs in hematopoietic neoplasms. In this review, we describe the preclinical and clinical advances recently made in the use of CDKIs. These include the FDA-approved CDK4/6 inhibitors, traditional and novel pan-CDKIs, as well as dual kinase inhibitors. We additionally provide an overview on molecular mechanisms of response vs. resistance and discuss open questions.

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Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion

Cited by 59 publications

References 40 publications

Molecular Strategies to Target Protein Aggregation in Huntington’s Disease

Molecular Strategies to Target Protein Aggregation in Huntington’s Disease

Targeting Protein Kinases Degradation by PROTACs

Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-)Clinical Application and Promising Approaches

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