From: Exploring the multiple roles of guardian of the genome: P53
S. No. | Name of the compound | Type of mutant | Mechanism | References |
---|---|---|---|---|
1 | HSP90 inhibitors (heat shock proteins) | R175H, L194F, R248Q, R273H, R280K, R172H (mouse) | “Reverse the HSP90’s function to inactivate MDM2 and CHIP”. | |
2 | HDAC inhibitors (histone deacetylase inhibitors) | R175H, R280K, V274F, P223L | These compounds target HDAC6 by inhibiting it and thus disrupting the HDAC6/HSP90/mutant P53 complex. “HDAC/HSP90 chaperone complex stabilizes mutant P53 by averting its degradation, which is mediated by E3 ubiquitin ligase”. “HDAC inhibitors or HSP90 inhibitors can disrupt this HDAC/HSP90 complex and induce degradation of mutant P53”. | [194–196] |
3 | Spautin-1 | R175H/C/D, S241F, R248Q/W/L, G245C, E258K, R273H/L, R280K, R282W | “Spautin-1 induces degradation of a broad range of mutant P53 proteins via the chaperone-mediated autophagy (CMA) pathway”. “Spautin-1 also induces cell death under non-proliferating conditions only when cancer cells carry mutant P53”. However, this effect of Spautin-1 is not dependent on MDM2 and the ubiquitin-proteasome pathway; instead, it is dependent on nuclear export of mutant P53 and the presence of Hsc70 (a member of the heat shock protein 70 families). | |
4 | MCB-613 | R175H | “MCB-613 preferentially targets mutant P53-R175H for lysosomal degradation by destabilizing the deubiquitinase USP15-mediated mutant P53 stabilization.” | [199] |
5 | Statins | V157F, R172H, R175H, Y220C, R248W, R273H, R280K | “Statins induce CHIP-dependent degradation of P53 with conformational alterations”. | [200] |
6 | Gambogic acid | R175H, G266E, R273H, R280K | “Gambogic acid targets and inhibits the mutant P53-Hsp90 complex and induces CHIP-dependent degradation or induce autophagy”. “Gambogic acid (GA) induces apoptosis and inhibits tumour growth in vitro by upregulating protein expression of wild-type P53”. | |
7 | YK-3-237 | V157F, M237I, R249S, R273H, R280K | “YK-3-237 reduces mutant P53 levels via deacetylation at lysine 382 by activating SIRT1”. “YK-3-237 induces cell cycle arrest and apoptosis in triple-negative breast cancer cell lines with enhanced expression of PUMA and NOXA.” | [204] |