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Table 2 Compounds that target mutant P53 and induce degradation of mutant P53

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”. [195, 196]
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). [197, 198]
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”. [201,202,203]
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]