Degradation of Androgen Receptor through Small Molecules for Prostate Cancer

Abstract

Prostate cancer is the most common carcinoma among aged males in western countries and more aggressive and lethal castration resistant prostate cancer often occurs after androgen deprivation therapy. The high expression of androgens and androgen receptor is closely related to prostate cancer. Efficient androgen receptor antagonists, such as enzalutamide and ARN-509, could be employed as potent anti-prostate cancer agents. Nevertheless, recent studies have revealed that F876L mutation in androgen receptor converts the action of enzalutamide and ARN-509 from an antagonist to agonist, so that novel strategies are urgent to address this resistance mechanism. In this review, we focus on the discussion about some novel strategies, which targets androgen receptor mainly through the degrading pathway as potential treatments for prostate cancer.

New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity

“…We prepared both the class II and III starting from a chiral hydroxyl bromide 11 (Scheme 1) reacted with an aniline (9 or 10) to form an R-bromoaniline (12 or 13), followed by oxirane (14 or 15) formation in the presence of K 2 CO 3 (or other basic conditions), via a known procedure. 27,37,47,48 In overview, compounds of II were prepared in very good yield by Method A via activation of substituted-1H-indoles (16) with sodium hydride and, its subsequent reaction with the oxiranes 14 or 15. Similarly, compounds of III were prepared by method B which uses LDA to activate substituted 1H-indolines (17) to react with the same oxiranes (14 or 15), as depicted in Scheme 1.…”

“…The lack of satisfactory hormonal pharmacotherapy for metastatic patients that have failed to respond to abiraterone and/or 5 and 6 [approved in February 2018] has piqued interest in the development of therapies to overcome Enz-R AR mutations. Some of the promising preclinical approaches include the following: (1) combination therapies, for example, sorafenib or CDK-4/6 inhibitors with 5 to revert the Enz-R phenotype; or (2) AR-directed monotherapies such as the emerging PROTACs technology that exploits cellular quality control machinery to selectively degrade specific target proteins , by creating in this case AR-PROTAC-E3 ubiquitin ligase ternary complexes; or (3) AR-independent approaches to treat CRPC, for example, by activating natural killer cells to attack the cancer; and each has shown promise in Enz-R or AR-V7 CRPC preclinical models. These approaches are still early in their development cycles, and many technical and regulatory hurdles remain for these approaches before any might reach the clinic for Enz-R patients.…”

“…Earlier this year, the AR antagonist 6 was approved for use in nonmetastatic CRPC based on its ability to extend the metastasis-free survival as compared to placebo. , Unfortunately, primary and acquired resistance to 5 (and other antiandrogens) is common, , for example, the mutations AR F876L or F876L-T877A switch 5 , at higher levels, from AR antagonist to agonist, making PCs enzalutamide-resistant (Enz-R) . Further, cross-resistance between 5 and 6 based on F876L and cross-resistance in general between abiraterone and/or ligand binding domain (LBD)directed antiandrogens are well known. − Moreover, AR splice variants (AR SVs; e.g., AR-V7 and D567es) lacking the LBD have been reported as pan-resistant CRPCs . The development of resistance to antiandrogens is a growing concern and new strategies to block AR function in CRPC are required. − …”

“…12,13 Unfortunately, primary and acquired resistance to 5 (and other antiandrogens) is common, 14,15 for example, the mutations AR F876L or F876L-T877A switch 5, at higher levels, from AR antagonist to agonist, making PCs enzalutamide-resistant (Enz-R). 14 Further, cross-resistance between 5 and 6 based on F876L 16 and cross-resistance in general between abiraterone and/or ligand binding domain (LBD)directed antiandrogens are well known. 17−19 Moreover, AR splice variants (AR SVs; e.g., AR-V7 and D567es) lacking the LBD have been reported as pan-resistant CRPCs.…”

Role of Small Molecule Targeted Compounds in Cancer: Progress, Opportunities, and Challenges

“…The high expression of androgens and androgen receptors (AR) is closely related to prostate carcinoma. Efficient AR antagonists, such as Enzalutamide and ARN-509, could be employed as potent anti-prostate carcinoma agents ( Ge et al, 2018 ). Selinexor, combined with Dexamethasone, has gained approval for patients with Penta-refractory multiple myeloma (MM) by FDA.…”