Abstract:Aldo-keto reductase 1C3 (AKR1C3) is overexpressed in castration-resistant prostate cancer where it acts to drive proliferation and aggressiveness by producing androgens. The reductive action of the enzyme leads to chemoresistance development against various clinical antineoplastics across a range of cancers. Herein, we report the continued optimization of selective AKR1C3 inhibitors and the identification of 5r, a potent AKR1C3 inhibitor (IC 50 = 51 nM) with >1216-fold selectivity for AKR1C3 over closely relat… Show more
“…S3c ). The disconnection between biochemical IC 50 and cellular inhibition effect can be rationalized by the cell penetration issues presented by a carboxylic acid containing compound, and this has been previously observed with other free acid AKR1C3 inhibitors and rectified with a prodrug strategy 25 .…”
Section: Resultsmentioning
confidence: 90%
“…Further structure-activity relationship studies identified the biphenyl derivative 3 with an AKR1C3 IC 50 = 43 nM with >2300-fold selectivity for AKR1C3 over AKR1C2, and is one of the most potent and selective inhibitors of AKR1C3 known to date (Fig. 1 ) 10 , 25 . Fig.…”
Aldo-keto reductase 1C3 (AKR1C3) is a protein upregulated in prostate cancer, hematological malignancies, and other cancers where it contributes to proliferation and chemotherapeutic resistance. Androgen receptor splice variant 7 (ARv7) is the most common mutation of the AR receptor that confers resistance to clinical androgen receptor signalling inhibitors in castration-resistant prostate cancer. AKR1C3 interacts with ARv7 promoting stabilization. Herein we report the discovery of the first-in-class AKR1C3 Proteolysis-Targeting Chimera (PROTAC) degrader. This first-generation degrader potently reduced AKR1C3 expression in 22Rv1 prostate cancer cells with a half-maximal degradation concentration (DC50) of 52 nM. Gratifyingly, concomitant degradation of ARv7 was observed with a DC50 = 70 nM, along with degradation of the AKR1C3 isoforms AKR1C1 and AKR1C2 to a lesser extent. This compound represents a highly useful chemical tool and a promising strategy for prostate cancer intervention.
“…S3c ). The disconnection between biochemical IC 50 and cellular inhibition effect can be rationalized by the cell penetration issues presented by a carboxylic acid containing compound, and this has been previously observed with other free acid AKR1C3 inhibitors and rectified with a prodrug strategy 25 .…”
Section: Resultsmentioning
confidence: 90%
“…Further structure-activity relationship studies identified the biphenyl derivative 3 with an AKR1C3 IC 50 = 43 nM with >2300-fold selectivity for AKR1C3 over AKR1C2, and is one of the most potent and selective inhibitors of AKR1C3 known to date (Fig. 1 ) 10 , 25 . Fig.…”
Aldo-keto reductase 1C3 (AKR1C3) is a protein upregulated in prostate cancer, hematological malignancies, and other cancers where it contributes to proliferation and chemotherapeutic resistance. Androgen receptor splice variant 7 (ARv7) is the most common mutation of the AR receptor that confers resistance to clinical androgen receptor signalling inhibitors in castration-resistant prostate cancer. AKR1C3 interacts with ARv7 promoting stabilization. Herein we report the discovery of the first-in-class AKR1C3 Proteolysis-Targeting Chimera (PROTAC) degrader. This first-generation degrader potently reduced AKR1C3 expression in 22Rv1 prostate cancer cells with a half-maximal degradation concentration (DC50) of 52 nM. Gratifyingly, concomitant degradation of ARv7 was observed with a DC50 = 70 nM, along with degradation of the AKR1C3 isoforms AKR1C1 and AKR1C2 to a lesser extent. This compound represents a highly useful chemical tool and a promising strategy for prostate cancer intervention.
A series of 7‐substituted coumarin derivatives have been characterized as pan‐aldo‐keto reductase family 1C (AKR1C) inhibitors. The AKR1C family of enzymes are overexpressed in numerous cancers where they are involved in drug resistance development. 7‐hydroxy coumarin ethyl esters and their corresponding amides have high potency for AKR1C3 and AKR1C2 inhibition. Coumarin amide 3a possessed IC50 values of 50 nM and 90 nM for AKR1C3 and AKR1C2, respectively, and exhibits ‘drug‐like’ metabolic stability and half‐life in human and mouse liver microsomes and plasma. Compound 3a was employed as a chemical tool to determine pan‐AKR1C2/3 inhibition effects both as a radiation sensitizer and as a potentiator of chemotherapy cytotoxicity. In contrast to previously reported pan‐AKR1C inhibitors, 3a demonstrated no radiation sensitization effect in a radiation‐resistant prostate cancer cell line model. Pan‐AKR1C inhibition also did not potentiate the in vitro cytotoxicity of ABT‐737, daunorubicin or dexamethasone, in two patient‐derived T‐cell ALL and pre‐B‐cell ALL cell lines. In contrast, a highly selective AKR1C3 inhibitor, compound K90, enhanced the cytotoxicity of both ABT‐737 and daunorubicin in the T‐cell ALL cell line model. Thus, the inhibitory profile of the AKR1C family inhibitor required to effect enhancement of chemotherapeutic cytotoxicity may be chemotherapeutic agent‐specific in leukemia.
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