New study below [1].
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Some years ago, I became interested in the possibility of androgen receptor [AR] down-regulation. For instance, resveratrol was said to control progression of PCa in a rat model by AR down-regulation [2].
In the pre-CRPC era of Lupron-refractory PCa, it was known that AR was often up-regulated in some way (AR amplification / overexpression / mutation). And I seem to remember that down-regulation was described in terms of actual degradation of the AR protein.
This seemed to be an attractive way of countering or reversing Lupron resistance, which occurs within 18-24 months for most men.
Of course, nothing came of it.
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The new paper concerns proteolysis targeting chimeras (PROTACs).
"Proteo-lysis" simply means the breakdown of a protein.
A "chimera" is an entity composed of two parts that don't normally belong together. In this case, two molecules, one of which performs the lysis.
While an AR antagonist (a "lutamide") invariably induces treatment-emergent resistance, a PROTEC does not. In addition, a much smaller amount of the drug is said to be sufficient to cause AR degradation.
"The compounds ... significantly inhibit enzalutamide-resistant growth of castration resistant prostate cancer (CRPC) cells. In castration-, enzalutamide-resistant CWR22Rv1 xenograft model without hormone ablation, ITRI-90 displays a pharmacokinetic profile with decent oral bioavailability and strong antitumor efficacy." [1]
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In 2020, a study looked at ARD-61 [3]:
"AR-targeting therapies. ARD-61 is the most potent of the AR degraders and effectively induces on-target AR degradation with a mechanism consistent with the PROTAC design. Compared to clinically-approved AR antagonists, administration of ARD-61 in vitro and in vivo results in more potent anti-proliferative, pro-apoptotic effects and attenuation of downstream AR target gene expression in prostate cancer cells. Importantly, we demonstrate that ARD-61 functions in enzalutamide-resistant model systems, characterized by diverse proposed mechanisms of resistance that include AR amplification/overexpression, AR mutation, and expression of AR splice variants, such as AR-V7. While AR degraders are unable to bind and degrade AR-V7, they continue to inhibit tumor cell growth in models overexpressing AR-V7. To further explore this, we developed several isogenic prostate cell line models in which AR-V7 is highly expressed, which also failed to influence the cell inhibitory effects of AR degraders, suggesting that AR-V7 is not a functional resistance mechanism for AR antagonism. These data provide compelling evidence that full-length AR remains a prominent oncogenic driver of prostate cancers which have developed resistance to AR antagonists and highlight the clinical potential of AR degraders for treatment of CRPC."
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Dimethylcurcumin (2021 [4])
"Dimethylcurcumin (ASC-J9) is a curcumin analogue capable of inhibiting prostate cancer cell proliferation. The mechanism is associated with the unique role of ASC-J9 in enhancing androgen receptor (AR) degradation. So far, ASC-J9 has been investigated in typical AR-associated diseases such as prostate cancer, benign prostatic hypertrophy, bladder cancer, renal diseases, liver diseases, cardiovascular diseases, cutaneous wound, spinal and bulbar muscular atrophy, ovarian cancer and melanoma, exhibiting great potentials in disease control. In this review, the effects and molecular mechanisms of ASC-J9 on various AR-associated diseases are summarized. Importantly, the effects of ASC-J9 and AR antagonists enzalutamide/bicalutamide on prostate cancer are compared in detail and crucial differences are highlighted. At last, the pharmacological effects of ASC-J9 are summarized and the future applications of ASC-J9 in AR-associated disease control are discussed."
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from Wiki [5]:
"A selective androgen receptor degrader ... (SARD) is a type of drug which interacts with the androgen receptor (AR) such that it causes the AR to be degraded and thus downregulated. They are under investigation for the treatment of prostate cancer and other androgen-dependent conditions.
As of 2017, dimethylcurcumin (ASC-J9), a SARD, is under development for the treatment of acne vulgaris." LOL
-Patrick
[1] pubmed.ncbi.nlm.nih.gov/368...
[2] pubmed.ncbi.nlm.nih.gov/184...
[3] ncbi.nlm.nih.gov/pmc/articl...
Pinostilbene inhibits the Enz-resistant CRPC cell line by inhibiting AR variant 7
Androgen Receptor Activity (ARA) for BAT