Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression

Qin, Chong; Hu, Yang; Zhou, Bing; Fernández‐Salas, Ester; Yang, Chao‐Yie; Liu, Liu; McEachern, Donna; Przybranowski, Sally; Wang, Mi; Stuckey, Jeanne A.; Meagher, Jennifer L.; Bai, Longchuan; Chen, Zhuo; Lin, Mei; Yang, Jiuling; Ziazadeh, Danya N.; Xu, Fuming; Hu, Jiantao; Xiang, Weidong; Huang, Liyue; Li, Siwei; Wen, Bo; Sun, Duxin; Wang, Shaomeng

doi:10.1021/acs.jmedchem.8b00506

Cited by 226 publications

(212 citation statements)

References 60 publications

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“…[ 148 ] Another BRD4‐targeted PROTAC ARV‐771 was synthesized with a BRD4 inhibitor and VHL ligand and experimental results showed rapid degradation of BRD2/3/4 in castration‐resistant prostate cancer. [ 149 ] Moreover, PROTAC QCA570 also induces BRD4 degradation in leukemia cells, [ 150 ] and PROTAC TD428, which comprises a novel CRBN ligand (TD‐106) linked to a BET inhibitor, JQ1, efficiently induces BET protein degradation in a prostate cancer cell line. [ 112 ]…”

Section: Strategies For Selective Protein Degradationmentioning

confidence: 99%

Significance of Selective Protein Degradation in the Development of Novel Targeted Drugs and Its Implications in Cancer Therapy

Yang

Wang

Feng

et al. 2020

Advanced Therapeutics

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The evolution of traditional chemotherapeutic drugs to targeted drugs has led to major changes in cancer treatment. However, it remains difficult to develop effective targeted drugs that can act against “undruggable” proteins, including some well‐known oncoproteins such as KRas. Moreover, mutations of target genes limit the use of targeted drugs. Although some strategies such as RNA interference and DNA editing have been adopted to solve these problems, their clinical use remains challenging. Therefore, new strategies are urgently needed to meet the dilemmas encountered in the use of targeted drugs. As protein degradation is a rapid and well‐regulated biological process in cells, targeting protein degradation by inducing cellular protein degradation machinery, regardless of the status of the target, is an attractive idea for developing novel targeted drugs. This review summarizes recent advances in targeted protein degradation, with a focus on the current reagents and strategies used for inducing selective degradation of target proteins to provide clues for the development of novel anticancer drugs and cancer therapies.

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Section: Strategies For Selective Protein Degradationmentioning

confidence: 99%

Significance of Selective Protein Degradation in the Development of Novel Targeted Drugs and Its Implications in Cancer Therapy

Yang

Wang

Feng

et al. 2020

Advanced Therapeutics

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“…Therefore, the development of high throughput methods for synthesis and characterization of PROTAC molecules will accelerate the development of new inhibitors. Limited in vivo data are available (Qin et al, 2018;Saenz et al, 2017); toxicity, pharmacokinetics, bioavailability, tissue distribution and metabolism of PROTAC molecules will require extensive investigation. The large size of PROTACs (~1000 Da) might affect cell permeability, potentially resulting in suboptimal presentation of a target to the E3 ligase; smaller PROTACs could improve cellular uptake and potency.…”

Section: Proteolysis-targeting Chimera (Protac)mentioning

confidence: 99%

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Veggiani

Gerpe

Sidhu

et al. 2019

Pharmacology & Therapeutics

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a b s t r a c t a r t i c l e i n f o Development of effective cancer therapeutic strategies relies on our ability to interfere with cellular processes that are dysregulated in tumors. Given the essential role of the ubiquitin proteasome system (UPS) in regulating a myriad of cellular processes, it is not surprising that malfunction of UPS components is implicated in numerous human diseases, including many types of cancer. The clinical success of proteasome inhibitors in treating multiple myeloma has further stimulated enthusiasm for targeting UPS proteins for pharmacological intervention in cancer treatment, particularly in the precision medicine era. Unfortunately, despite tremendous efforts, the paucity of potent and selective UPS inhibitors has severely hampered attempts to exploit the UPS for therapeutic benefits. To tackle this problem, many groups have been working on technology advancement to rapidly and effectively screen for potent and specific UPS modulators as intracellular probes or early-phase therapeutic agents. Here, we review several emerging technologies for developing chemical-and protein-based molecules to manipulate UPS enzymatic activity, with the aim of providing an overview of strategies available to target ubiquitination for cancer therapy.

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“…Typically a binder for which a co-crystal structure was available to define a suitable exit vector for the installation of the linker. From the E3 binding side, the vast majority of PROTACs are limited to just two ligases: CRBN which is targeted by various immunomodulatory drugs (IMiDs) such as thalidomide 9 , pomalidomide 10 or lenalidomide 11,12 and VHL for which highaffinity small molecule ligands were developed 13,14 .…”

Section: Introductionmentioning

confidence: 99%

PRosettaC: Rosetta based modeling of PROTAC mediated ternary complexes

Zaidman

London

2020

Preprint

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Proteolysis-targeting chimeras (PROTACs), which induce degradation by recruitment of an E3 ligase to a target protein, are gaining much interest as a new pharmacological modality. However, designing PROTACs is challenging. Formation of a ternary complex between the protein target, the PROTAC and the recruited E3 ligase is considered paramount for successful degradation. A structural model of this ternary complex could in principle inform rational PROTAC design. Unfortunately, only a handful of structures are available for such complexes, necessitating tools for their modeling. We developed a combined protocol that alternates between sampling of the protein-protein interaction space and the PROTAC molecule conformational space. Application of this protocol -PRosettaC -to a benchmark of known PROTAC ternary complexes results in near-native predictions, with often atomic accuracy prediction of the protein chains, as well as the PROTAC binding moieties. It allowed the modeling of a CRBN/BTK complex that recapitulated experimental results for a series of PROTACs. PRosettaC generated models may be used to design PROTACs for new targets, as well as improve PROTACs for existing targets, potentially cutting down time and synthesis efforts.

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Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression

Cited by 226 publications

References 60 publications

Significance of Selective Protein Degradation in the Development of Novel Targeted Drugs and Its Implications in Cancer Therapy

Significance of Selective Protein Degradation in the Development of Novel Targeted Drugs and Its Implications in Cancer Therapy

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

PRosettaC: Rosetta based modeling of PROTAC mediated ternary complexes

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