Rosolutamide (ASC-JM17) is an orally active Nrf1/Nrf2 activator. Rosolutamide activates Hsf1 pathways, upregulates proteasome subunits and antioxidant enzymes, induces proteasome complex structural rearrangement, and enhances ubiquitin-proteasome system-mediated degradation. Rosolutamide reduces mutant androgen receptor and ataxin-3 aggregates, restores mitochondrial function, attenuates reactive oxygen species ( ROS ) levels, induces apoptosis and ferroptosis, and inhibits cancer cell growth. Rosolutamide can be used for the research of spinal and bulbar muscular atrophy, Huntington’s disease, and temozolomide-resistant glioblastoma [1] [2] [3] [4].
In Vivo, Rosolutamide (50 nM; incorporated into fly food; continuous exposure throughout development/ adulthood) rescues mutant AR-induced toxicity in Drosophila SBMA models, and this protective effect requires the Nrf1/Nrf2 ortholog CncC but not Hsf1[1]. Rosolutamide (120 mg/kg; i.g.; daily; 6 weeks or 16 weeks) ameliorates disease manifestations, reduces mutant AR accumulation, and activates Nrf1/Nrf2 pathways in symptomatic AR97Q mice[1].
In Vitro, Rosolutamide (0.2-5 μM; 0-12 h) accelerates UPS-mediated clearance of wild-type and polyglutamine-expanded androgen receptor in healthy control and SBMA fibroblasts, reducing AR steady-state levels and half-life[1]. Rosolutamide (5 μM) inhibits the transcriptional activity of wild-type and polyglutamine-expanded androgen receptor in DHT-treated PC12 cells[1]. Rosolutamide (0-40 μM) potently activates the heat shock response pathway in PC12 cells[1]. Rosolutamide (0-7.5 μM) activates Nrf1 to increase expression of multiple proteasome subunits in PC12 and MCF7 cells[1]. Rosolutamide enhances chymotrypsin-like, trypsin-like, and caspase-like proteasome catalytic activities in PC12 cells[1]. Rosolutamide (0-7.5 μM) activates Nrf2 to increase expression of antioxidant enzymes HO-1, Nqo1, Gclc, and catalase in PC12 cells without inducing global oxidative protein damage[1]. Rosolutamide (2.5 μM; 16 h) protects MCF7 cells against hydrogen peroxide-induced oxidative stress via Nrf2 activation[1]. Rosolutamide (0-7.5 μM) activates Hsf1 to increase expression of heat shock proteins Hsp25, Hsp40, Hsp72, Hsp90, and co-chaperone Hop in PC12 and MCF7 cells[1]. Rosolutamide (0.3-5 µM; 24 h) shows no cytotoxicity in WT, MJD26, and MJD78 cells, but induces cytotoxicity at concentrations greater than 5 µM in WT and MJD78 cells[3]. Rosolutamide (0.3-5 µM; 24 h) improves mitochondrial respiration function in MJD78 cells[3]. Rosolutamide (0.3-5 µM; 24 h) reduces mutant ataxin-3 protein expression and protein aggregation in MJD78 cells via induction of autophagy, with no effect on ATXN3 mRNA levels[3]. Rosolutamide (0.3-5 µM; 24 h) reduces oxidative stress in MJD78 cells by lowering total and mitochondrial ROS levels, and enhances antioxidant defenses by increasing NQO1, HO-1, SOD2, GSH, and catalase, with 1 µM showing the strongest effects[3]. Rosolutamide (0.3-5 µM; 24 h) activates Nrf2 in a dose-dependent manner in MJD78 cells, increasing Nrf2 transcriptional activity[3].
References:
[1]. Bott LC, et al. A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy. Hum Mol Genet. 2016;25(10):1979-1989.
[2]. Sedlacek J. Activation of the 26S Proteasome to Reduce Proteotoxic Stress and Improve the Efficacy of PROTACs. ACS Pharmacol Transl Sci. 2024 Dec 16;8(1):21-35.
[3]. Wu YL, et al. In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3. Antioxidants (Basel). 2022;11(7):1389. Published 2022 Jul 18.
[4]. Osifová Z, et al. Diketo-Ketoenol Tautomers in Curcuminoids: Synthesis, Separation of Tautomers, and Kinetic and Structural Studies. J Org Chem. 2022 Aug 5;87(15):10309-10318.
In Vivo, Rosolutamide (50 nM; incorporated into fly food; continuous exposure throughout development/ adulthood) rescues mutant AR-induced toxicity in Drosophila SBMA models, and this protective effect requires the Nrf1/Nrf2 ortholog CncC but not Hsf1[1]. Rosolutamide (120 mg/kg; i.g.; daily; 6 weeks or 16 weeks) ameliorates disease manifestations, reduces mutant AR accumulation, and activates Nrf1/Nrf2 pathways in symptomatic AR97Q mice[1].
In Vitro, Rosolutamide (0.2-5 μM; 0-12 h) accelerates UPS-mediated clearance of wild-type and polyglutamine-expanded androgen receptor in healthy control and SBMA fibroblasts, reducing AR steady-state levels and half-life[1]. Rosolutamide (5 μM) inhibits the transcriptional activity of wild-type and polyglutamine-expanded androgen receptor in DHT-treated PC12 cells[1]. Rosolutamide (0-40 μM) potently activates the heat shock response pathway in PC12 cells[1]. Rosolutamide (0-7.5 μM) activates Nrf1 to increase expression of multiple proteasome subunits in PC12 and MCF7 cells[1]. Rosolutamide enhances chymotrypsin-like, trypsin-like, and caspase-like proteasome catalytic activities in PC12 cells[1]. Rosolutamide (0-7.5 μM) activates Nrf2 to increase expression of antioxidant enzymes HO-1, Nqo1, Gclc, and catalase in PC12 cells without inducing global oxidative protein damage[1]. Rosolutamide (2.5 μM; 16 h) protects MCF7 cells against hydrogen peroxide-induced oxidative stress via Nrf2 activation[1]. Rosolutamide (0-7.5 μM) activates Hsf1 to increase expression of heat shock proteins Hsp25, Hsp40, Hsp72, Hsp90, and co-chaperone Hop in PC12 and MCF7 cells[1]. Rosolutamide (0.3-5 µM; 24 h) shows no cytotoxicity in WT, MJD26, and MJD78 cells, but induces cytotoxicity at concentrations greater than 5 µM in WT and MJD78 cells[3]. Rosolutamide (0.3-5 µM; 24 h) improves mitochondrial respiration function in MJD78 cells[3]. Rosolutamide (0.3-5 µM; 24 h) reduces mutant ataxin-3 protein expression and protein aggregation in MJD78 cells via induction of autophagy, with no effect on ATXN3 mRNA levels[3]. Rosolutamide (0.3-5 µM; 24 h) reduces oxidative stress in MJD78 cells by lowering total and mitochondrial ROS levels, and enhances antioxidant defenses by increasing NQO1, HO-1, SOD2, GSH, and catalase, with 1 µM showing the strongest effects[3]. Rosolutamide (0.3-5 µM; 24 h) activates Nrf2 in a dose-dependent manner in MJD78 cells, increasing Nrf2 transcriptional activity[3].
References:
[1]. Bott LC, et al. A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy. Hum Mol Genet. 2016;25(10):1979-1989.
[2]. Sedlacek J. Activation of the 26S Proteasome to Reduce Proteotoxic Stress and Improve the Efficacy of PROTACs. ACS Pharmacol Transl Sci. 2024 Dec 16;8(1):21-35.
[3]. Wu YL, et al. In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3. Antioxidants (Basel). 2022;11(7):1389. Published 2022 Jul 18.
[4]. Osifová Z, et al. Diketo-Ketoenol Tautomers in Curcuminoids: Synthesis, Separation of Tautomers, and Kinetic and Structural Studies. J Org Chem. 2022 Aug 5;87(15):10309-10318.