Design, synthesis, and biological evaluation of phenyl thiazole-based AR-V7 degraders

Bhumireddy, Archana; Bandaru, Naga Venkata Madhusudhan Rao; Reddy, Bobby; Gore, Suraj T; Mukherjee, Subhendu; Balasubramanian, Wesley Roy; Kumar, Vipin; Alapati, Krishna Satya; Sekhar, Kondapalli Venkata Gowri Chandra; Nellore, Kavitha; Abbineni, Chandrasekhar; Samajdar, Susanta

doi:10.1016/j.bmcl.2021.128448

Cited by 13 publications

(13 citation statements)

References 26 publications

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“…We next tested both degraders in the androgen-resistant prostate cancer cell line 22Rv1 that expresses wildtype AR and AR-V7 and demonstrated that both JP-2-217 and JP-2-224, but not VPC-14228 or a previously reported VHL-based AR-V7 PROTAC (compound 6) 38 , degraded both wild-type AR and AR-V7 (Figure 8i-8j; Figure S6a-S6d). Overall, we demonstrated that the minimal covalent handle JP-2-196 could be used to convert protein targeting ligands into molecular glue degraders of several proteins from different protein classes.…”

Section: Transplanting Covalent Chemical Handle Onto Protein-targetin...mentioning

confidence: 93%

“…AR-V7 is considered to be a relatively undruggable target, given that the ligand binding domain that is the target of most AR-targeting drugs is missing from AR-V7. We linked our fumarate derivative JP-2-196 onto a previously discovered DNA-binding domain ligand, VPC-14228, for the androgen receptor that had recently been used in several VHL-based PROTACs to degrade AR-V7, through two different types of linkages to yield JP-2-217 and JP-2-224 (Figure 8e) [36][37][38] . Both of these compounds showed potent binding to pure RNF126 protein (Figure 8f).…”

Section: Transplanting Covalent Chemical Handle Onto Protein-targetin...mentioning

confidence: 99%

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Rational Chemical Design of Molecular Glue Degraders

Toriki

Papatzimas

Nishikawa

et al. 2022

Preprint

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Targeted protein degradation with molecular glue degraders has arisen as powerful therapeutic modality for eliminating classically undruggable disease-causing proteins through proteasome-mediated degradation. However, we currently lack rational chemical design principles for converting protein-targeting ligands into molecular glue degraders. To overcome this challenge, we sought to identify chemical handles that would convert protein-targeting ligands into molecular glue degraders of their targets. Using the CDK4/6 inhibitor Ribociclib as a testbed, we identified a covalent handle that, when appended to the exit vector of Ribociclib, induced the proteasome-mediated degradation of CDK4 in cancer cells. Covalent chemoproteomic profiling of this CDK4 degrader revealed covalent interactions with cysteine 32 of the RING family E3 ubiquitin ligase RNF126. Optimization of this covalent scaffold led to an improved CDK4 degrader with a methoxyphenyl fumarate handle that showed improved interactions with RNF126. We then identified the minimum covalent chemical handle required for interaction with RNF126. With this knowledge in hand, we transplanted this covalent fumarate handle onto chemically related and un-related protein-targeting ligands to induce the degradation of several proteins across diverse protein classes, including BRD4, BCR-ABL and c-ABL, PDE5, AR and AR-V7, BTK, LRRK2, and SMARCA2. Our study undercovers a potential chemical rational design strategy for converting protein-targeting ligands into covalent molecular glue degraders.

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Section: Transplanting Covalent Chemical Handle Onto Protein-targetin...mentioning

confidence: 93%

Section: Transplanting Covalent Chemical Handle Onto Protein-targetin...mentioning

confidence: 99%

Rational Chemical Design of Molecular Glue Degraders

Toriki

Papatzimas

Nishikawa

et al. 2022

Preprint

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“…developed a selective AR-V7 degrader, PROTAC 15 ( Table 3 ) with DC 50 of 0.32 µM by recruiting VHL E3 ligase to AR DBD binder. 52 This molecule effectively degraded AR-V7 in a CRPC cell line and demonstrated good oral bioavailability in mouse PK studies. This tool compound can be used to evaluate the pharmacological effects of AR-V7 degraders.…”

Section: Protacs For Cancersmentioning

confidence: 97%

Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges

Wang

Zhang

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Proteolysis-targeting chimaeras (PROTACs) have been developed to be an emerging technology for targeted protein degradation and attracted the favour of academic institutions, large pharmaceutical enterprises, and biotechnology companies. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The heterobifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. To date, PROTACs targeting ∼70 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for diseases therapy. In this review, the recent advances in PROTACs against clinically validated drug targets are summarised and the chemical structure, cellular and in vivo activity, pharmacokinetics, and pharmacodynamics of these PROTACs are highlighted. In addition, the potential advantages, challenges, and prospects of PROTACs technology in disease treatment are discussed.

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“…4 ) based on AR-DBD binder VPC-14228. 30 The DC 50 was 0.32 µM for AR-V7 protein in 22Rv1 cells and 14 was found to have modest oral bioavailability.…”

Section: Protacs Targeting Cancer-related Targetsmentioning

confidence: 98%

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Cao

et al. 2022

Sig Transduct Target Ther

112

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PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but also provide unique chemical knockdown tools for biological research in a catalytic, reversible, and rapid manner. In 2019, our group published a review article “PROTACs: great opportunities for academia and industry” in the journal, summarizing the representative compounds of PROTACs reported before the end of 2019. In the past 2 years, the entire field of protein degradation has experienced rapid development, including not only a large increase in the number of research papers on protein-degradation technology but also a rapid increase in the number of small-molecule degraders that have entered the clinical and will enter the clinical stage. In addition to PROTAC and molecular glue technology, other new degradation technologies are also developing rapidly. In this article, we mainly summarize and review the representative PROTACs of related targets published in 2020–2021 to present to researchers the exciting developments in the field of protein degradation. The problems that need to be solved in this field will also be briefly introduced.

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Design, synthesis, and biological evaluation of phenyl thiazole-based AR-V7 degraders

Cited by 13 publications

References 26 publications

Rational Chemical Design of Molecular Glue Degraders

Rational Chemical Design of Molecular Glue Degraders

Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

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