Effects of MTX-23, a Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to Second-Line Antiandrogen Therapy

Lee, Geun Taek; Nagaya, Naoya; Desantis, Jenny; Madura, Kiran; Sabaawy, Hatem E.; Kim, Wun-Jae; Vaz, Roy J.; Cruciani, Gabriele; Kim, Isaac Yi

doi:10.1158/1535-7163.mct-20-0417

Cited by 62 publications

(45 citation statements)

References 45 publications

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“…Liu, C, et al showed that targeting the HSP70/STUB1 with ARVib can potently trigger AR/AR-V7 degradation, thereby suppressing proliferation and progression of CRPC 37 . Moreover, other groups showed that the application of proteolysis-targeting chimera (PROTAC) technique designed for the degradation of AR 38 , AR-V7 39 , and BET family proteins 40 displays favorable anti-CRPC activities. Unlike these findings, we here identify SNS-032 as a degradation inducer of SIX1, a new recognized oncogenic driver of CRPC, and update the knowledge and approach to CRPC treatment.…”

Section: Discussionmentioning

confidence: 99%

A SIX1 degradation inducer blocks excessive proliferation of prostate cancer

et al. 2022

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Prostate cancer (PC) remains a great medical challenge due to its high incidence and the development of castration resistance in patients treated with androgen deprivation therapy. Deubiquitinases, the enzymes that specifically hydrolyze ubiquitin chains on their substrates, were recently proposed as a serious of critical therapeutic targets for cancer treatment. Our previous study has been reported that the ubiquitin specific peptidase 1 (USP1) functionally acts as a deubiquitinase of sine oculis homeobox homolog 1 (SIX1) and contributes to the proliferation and castration resistance of PC. The stabilization of SIX1 by USP1 partially depends on the status of glucose-regulated protein 75 (GRP75). In this study, we aimed to identify a SIX1 degradation inducer via inhibiting the USP1-SIX1 axis. we screened a range of kinase inhibitors and showed that SNS-032 is the best candidate to trigger the ubiquitinated degradation of SIX1. SNS-032 not only restrains activity of the USP1-SIX1 axis and cell cycle progression, but also results in apoptosis of PC cells. Moreover, the combination of SNS-032 and enzalutamide synergistically induces apoptosis and downregulates expression of USP1, SIX1, and AR/AR-V7 in AR-V7 highly expressed 22Rv1 cells. Overall, our findings may develop a novel and effective strategy to overcome castration resistance in PC for the identification of a SIX1 degradation inducer via targeting the USP1-SIX1 axis.

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Section: Discussionmentioning

confidence: 99%

A SIX1 degradation inducer blocks excessive proliferation of prostate cancer

et al. 2022

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“…However, the AR antagonists-derived PROTACs will not be effective in CRPC with AR-SVs such as AR-V7 that lack the LBD. To this end, MTX-23 ( Figure 3 ), a VHL-recruiting AR-PROTAC based on a ligand targeting the DNA binding domain (DBD), has been developed to induce degradation of AR-V7 ( Lee et al, 2021 ). MTX-23 is effective in inhibiting cell growth in multiple resistance PC cell lines and shows efficacy in tumor models.…”

Section: Protacs Targeted Towards Treatment Of Various Types Of Drug ...mentioning

confidence: 99%

Overcoming Cancer Drug Resistance Utilizing PROTAC Technology

Burke

Smith

Zheng

2022

Front. Cell Dev. Biol.

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Cancer drug resistance presents a major barrier to continued successful treatment of malignancies. Current therapies inhibiting proteins indicated in cancer progression are consistently found to lose efficacy as a result of acquired drug resistance, often caused by mutated or overexpressed protein targets. By hijacking the cellular ubiquitin-proteasome protein degradation machinery, proteolysis-targeting chimeras (PROTACs) offer an alternative therapeutic modality to cancer treatments with various potential advantages. PROTACs specific for a number of known cancer targets have been developed in the last 5 years, which present new options for remission in patients with previously untreatable malignancies and provide a foundation for future-generation compounds. One notable advantage of PROTACs, supported by evidence from a number of recent studies, is that they can overcome some of the resistance mechanisms to traditional targeted therapies. More recently, some groups have begun researching the use of PROTACs to successfully degrade mutated targets conferring cancer resistance against first-line treatments. In this review, we focus on analyzing the developments in PROTACs geared towards cancer resistance and targets that confer it in the search for new and successful therapies.

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“…Other AR-targeted PROTAC molecules with animal testing data include TD-802 (DC 50 = 12.5 nM) ( 32 ) and A031 (IC 50 < 0.25 μM) ( 33 ) that promote degradation of the full-length AR protein. MTX-23 was shown to promote protein degradation of both the full-length and AR-V7 variant AR protein (DC 50 = 0.37-2 μM) ( 34 ). In addition, three PROTAC molecules, A9/A16 ( 35 , 36 ) and AR SNIPER-51 compounds ( 37 ), were only tested in cell culture models.…”

Section: Ar Protein Elimination Approaches In Preclinical Development...mentioning

confidence: 99%

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

Huang

Lin

2022

Front. Oncol.

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Prostate cancer is a major health issue in western countries and is the second leading cause of cancer death in American men. Prostate cancer depends on the androgen receptor (AR), a transcriptional factor critical for prostate cancer growth and progression. Castration by surgery or medical treatment reduces androgen levels, resulting in prostatic atrophy and prostate cancer regression. Thus, metastatic prostate cancers are initially managed with androgen deprivation therapy. Unfortunately, prostate cancers rapidly relapse after castration therapy and progress to a disease stage called castration-resistant prostate cancer (CRPC). Currently, clinical treatment for CRPCs is focused on suppressing AR activity with antagonists like Enzalutamide or by reducing androgen production with Abiraterone. In clinical practice, these treatments fail to yield a curative benefit in CRPC patients in part due to AR gene mutations or splicing variations, resulting in AR reactivation. It is conceivable that eliminating the AR protein in prostate cancer cells is a promising solution to provide a potential curative outcome. Multiple strategies have emerged, and several potent agents that reduce AR protein levels were reported to eliminate xenograft tumor growth in preclinical models via distinct mechanisms, including proteasome-mediated degradation, heat-shock protein inhibition, AR splicing suppression, blockage of AR nuclear localization, AR N-terminal suppression. A few small chemical compounds are undergoing clinical trials combined with existing AR antagonists. AR protein elimination by enhanced protein or mRNA degradation is a realistic solution for avoiding AR reactivation during androgen deprivation therapy in prostate cancers.

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Effects of MTX-23, a Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to Second-Line Antiandrogen Therapy

Cited by 62 publications

References 45 publications

A SIX1 degradation inducer blocks excessive proliferation of prostate cancer

A SIX1 degradation inducer blocks excessive proliferation of prostate cancer

Overcoming Cancer Drug Resistance Utilizing PROTAC Technology

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

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