Androgen receptor-directed molecular conjugates for targeting prostate cancer
TLDR
This review focuses on two classes of compounds: small-molecules and AR-ligand based conjugates that reduce AR expression, which allow down-regulation of AR levels by activating its proteasome-mediated degradation.Abstract:Â
Due to its central role in the cellular biology of prostate cancer (PC), androgen receptor (AR) still remains an important therapeutic target for fighting this tumor. Several drugs targeting AR have been reported so far, and many new molecules are expected for the future. In spite of their antitumor efficacy, these drugs are not selective for malignant cells and are subjected to AR-mediated activation of drug resistance mechanisms that are responsible for several drawbacks, including systemic toxicity and disease recurrence and metastasis. Among the several strategies considered to overcome these drawbacks, very appealing appears the design of hybrid small-molecule conjugates targeting AR to drive drug action on receptor-positive PC cells. These compounds are designed around on an AR binder, which selectively engages AR with high potency, coupled with a moiety endowed with different pharmacological properties. In this review we focus on two classes of compounds: a) small-molecules and AR-ligand based conjugates that reduce AR expression, which allow down-regulation of AR levels by activating its proteasome-mediated degradation, and b) AR-ligand-based conjugates for targeting small-molecules, in which the AR binder tethers small-molecules, including conventional antitumor drugs (e.g., cisplatin, doxorubicin, histone deacetylase inhibitors, as well as photo-sensitizers) and selectively directs drug action toward receptor-positive PC cells.read more
Citations
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Metabolic Plasticity in Chemotherapy Resistance.
TL;DR: The best-known cancer metabolic profiles are gone and several studies that reported tumors sensitization to chemotherapy by modulating metabolic pathways are discussed to help to rationalize the use of metabolic modulators to overcome therapy resistance.
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An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer.
Michael L. Mohler,Arunima Sikdar,Suriyan Ponnusamy,Dong Jin Hwang,Yali He,Duane D. Miller,Ramesh Narayanan +6 more
TL;DR: A recent review as mentioned in this paper discusses new developments in the prostate cancer treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or non-canonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs).
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Management of men with metastatic castration-resistant prostate cancer following potent androgen receptor inhibition: a review of novel investigational therapies.
TL;DR: Based on a review of the literature, exciting new therapeutic strategies exist for the treatment of mCRPC and in particular, PARPi, AR degraders, PSMA-targeted therapies, immune-directed therapies, and agents targeting resistance mechanisms as monotherapy or in combination could improve patient outcomes.
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Recent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer.
Daisuke Obinata,Daisuke Obinata,Mitchell G. Lawrence,Mitchell G. Lawrence,Mitchell G. Lawrence,Ken-ichi Takayama,Nicholas Choo,Gail P. Risbridger,Gail P. Risbridger,Gail P. Risbridger,Satoru Takahashi,Satoshi Inoue +11 more
TL;DR: The mechanisms of drug resistance in the AR signaling pathway, the intersection with collaborative TFs, and the use of patient-derived models for novel drug discovery are reviewed.
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Current Status and Future Perspectives of Androgen Receptor Inhibition Therapy for Prostate Cancer: A Comprehensive Review
TL;DR: The interaction between AR signaling and other molecular pathways involved in tumor pathogenesis and its clinical implications in metastasis and advanced disease will be discussed, along with a thorough overview of current and ongoing novel treatments for AR signaling inhibition as mentioned in this paper.
References
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Journal ArticleDOI
Global cancer statistics
TL;DR: A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination, and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake.
Journal ArticleDOI
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
Journal ArticleDOI
Emerging Mechanisms of Resistance to Androgen Receptor Inhibitors in Prostate Cancer
TL;DR: This Review highlights emerging mechanisms of acquired resistance to contemporary therapies targeting the AR pathway, which fall into the three broad categories of restored AR signalling, AR bypass signalling and complete AR independence.
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Induced protein degradation: an emerging drug discovery paradigm
Ashton C. Lai,Craig M. Crews +1 more
TL;DR: Induced protein degradation has the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.
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PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer.
Kanak Raina,Jing Lu,Yimin Qian,Martha Altieri,Deborah M. Gordon,Ann Marie Rossi,Jing Wang,Xin Chen,Hanqing Dong,Kam W. Siu,James D. Winkler,Andrew P. Crew,Craig M. Crews,Kevin Coleman +13 more
TL;DR: This study proves that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition.