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MCL1 PROTAC ChemRxiv.pdf (1.22 MB)
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From Inhibition to Degradation: Targeting the Anti-apoptotic Protein Myeloid Cell Leukemia 1(MCL1)

preprint
submitted on 14.02.2019 and posted on 15.02.2019 by James Papatzimas, Evgueni Gorobets, Ranjan Maity, Mir Ishruna Muniyat, Justin L. MacCallum, Paola Neri, Nizar J. Bahlis, Darren Derksen

Here we show the development of heterobifunctional small molecules capable of selectively targeting MCL1 using a Proteolysis Targeting Chimera (PROTAC) methodology leading to successful degradation. We have confirmed the involvement of the E3 ligase CUL4A-DDB1 cereblon (CRBN) ubiquitination pathway, making these PROTACs a first step toward a new class of anti-apoptotic BCL-2 family protein degraders.

Funding

Multiple Myeloma Research Foundation

Natural Sciences and Engineering Research Council of Canada (NSERC)

Natural Sciences and Engineering Research Council

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Canadian Institutes of Health Research (CIHR)

Arnie Charbonneau Cancer Research Institute

Alberta Children's Hospital Research Institute

Alberta Children's Hospital Foundation

Alberta Innovates Technology Futures

History

Email Address of Submitting Author

dderksen@ucalgary.ca

Institution

University of Calgary

Country

Canada

ORCID For Submitting Author

0000-0002-5945-6921

Declaration of Conflict of Interest

No conflict of interest

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