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      Design, Synthesis, and Biological Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Dual Degradation of IGF-1R and Src

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          Abstract

          A focused PROTAC library was developed to degrade both IGF-1R and Src proteins, which are associated with various cancers. PROTACs with IGF-1R and Src degradation potentials were synthesized by tethering different inhibitor warhead units and the E3 ligase (CRBN) recruiting-pomalidomide with various linkers. The designed PROTACs 12a–b inhibited the proliferation and migration of MCF7 and A549 cancer cells with low micromolar potency (1–5 μM) in various cellular assays.

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          Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.

          K M Sakamoto, K. -B. Kim, A Kumagai … (2001)
          The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF complex for ubiquitination and degradation. To this end, we tested methionine aminopeptidase-2 (MetAP-2), which covalently binds the angiogenesis inhibitor ovalicin. A chimeric compound, protein-targeting chimeric molecule 1 (Protac-1), was synthesized to recruit MetAP-2 to SCF. One domain of Protac-1 contains the I kappa B alpha phosphopeptide that is recognized by the F-box protein beta-TRCP, whereas the other domain is composed of ovalicin. We show that MetAP-2 can be tethered to SCF(beta-TRCP), ubiquitinated, and degraded in a Protac-1-dependent manner. In the future, this approach may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.
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            Induced protein degradation: an emerging drug discovery paradigm

            Ashton C Lai, Craig M Crews (2016)
            Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function. This article discusses emerging technologies, such as proteolysis-targeting chimaeras (PROTACs), that exploit cellular quality control machinery to selectively degrade target proteins, which could have advantages over traditional approaches, including the potential to target proteins that are not currently therapeutically tractable.
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              Catalytic in vivo protein knockdown by small-molecule PROTACs.

              Daniel Bondeson, Alina Mares, Ian E D Smith … (2015)
              The current predominant therapeutic paradigm is based on maximizing drug-receptor occupancy to achieve clinical benefit. This strategy, however, generally requires excessive drug concentrations to ensure sufficient occupancy, often leading to adverse side effects. Here, we describe major improvements to the proteolysis targeting chimeras (PROTACs) method, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target's ubiquitination and degradation. These compounds behave catalytically in their ability to induce the ubiquitination of super-stoichiometric quantities of proteins, providing efficacy that is not limited by equilibrium occupancy. We present two PROTACs that are capable of specifically reducing protein levels by >90% at nanomolar concentrations. In addition, mouse studies indicate that they provide broad tissue distribution and knockdown of the targeted protein in tumor xenografts. Together, these data demonstrate a protein knockdown system combining many of the favorable properties of small-molecule agents with the potent protein knockdown of RNAi and CRISPR.
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                Author and article information

                Contributors
                Qiao-Hong Chen: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 23 April 2020
                Publication date Collection: April 2020
                Volume: 25
                Issue: 8
                Electronic Location Identifier: 1948
                Affiliations
                [1 ]College of Pharmacy, Research Institute of Pharmaceutical sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea; sudhakariiim@ 123456gmail.com (S.M.); nklee12@ 123456snu.ac.kr (N.K.L.)
                [2 ]Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Korea; dongchanoh@ 123456snu.ac.kr
                Author notes
                [* ]Correspondence: jyleeut@ 123456snu.ac.kr ; Tel.: +82-02-880-2471
                [†]

                These authors contributed equally to this work.

                Article
                Publisher ID: molecules-25-01948
                DOI: 10.3390/molecules25081948
                PMC ID: 7221895
                PubMed ID: 32340152
                SO-VID: 4f46eef3-4996-449d-bfd2-f7589ea0cb58
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 30 March 2020
                Date accepted : 20 April 2020
                Categories
                Subject: Article

                Keywords: protacs,anticancer activity,protein degradation,igf-1r,src
                Data availability:
                Keywords: protacs, anticancer activity, protein degradation, igf-1r, src

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