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Table 1 Compounds that target mutant P53 and induce reactivation

From: Exploring the multiple roles of guardian of the genome: P53

S. No. Name of the compound Type of mutant Chemical name or class Mechanism References
1 CP-31398 V173A, S241F, R249S, R273H Styrylquinazoline “Stabilizes the DNA-binding core domain by promoting the proper folding of mutant P53 protein and triggering the P21 expression as well as inducing P53 reporter gene activity”. It is the first molecule discovered that can reactivate mutant P53. It also exhibits anti-tumour activity in a mouse model of melanoma xenograft tumour and colon carcinoma as well as in urothelial bladder cancer that developed in SV40 large T transgenic mice. Currently, there are no undergoing clinical trials for this compound. [165, 166]
2 STIMA-1 (SH group-targeting compound that induces massive apoptosis R175H, R273H Styrylquinazoline STIMA-1 stabilizes wild-type P53 conformation by binding to the cysteine residues in the DNA-binding core domain and thus reinstates its transcriptional activity. STIMA-1 is a derivative of CP-31398. “It also induces the upregulation of mRNA expression of P21, PUMA, and BAX that results in mutant P53 dependent apoptosis”. [167]
3 PRIMA-1 R273H, R175H, R248Q Quinuclidinone “PRIMA-1 stimulates the refolding of mutant P53 and increases the expression of BAX, PUMA, and CDK1NA in cancer cells”. “PRIMA is a prodrug that converts to its active form methylene Quinuclidinone (MQ) via hydrolysis and forms adducts with mutant P53 protein by Michael addition resulting in the reinstallation of wild-type P53 conformation and activation of apoptosis”. [168, 169]
4 APR-246 (PRIMA-1Met) R273H, R175H Quinuclidinone APR-246 is a methylated form of PRIMA-1 and exhibits higher efficacy in terms of reactivating mutant P53 and promoting apoptosis. “It is also transformed to reactive electrophile MQ and binds covalently to cysteine 277 (Cys277) in P53. APR-246 also displays anticancer effect via depletion of glutathione content and elevation of Reactive oxygen species (ROS), leading to oxidative damage to cancer cells”. It is a mutant-P53 independent effect. APR-246 is currently undergoing phase II clinical trials in combination with azacitidine (AZA) in patients who present with TP53 mutant acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). One trial is ongoing in France ( identifier NCT03588078) and another trial in the USA ( identifier NCT03072043). [170,171,172,173,174]
5 MIRA-1 R175H, R248Q, R273H Maleimide MIRA-1, like STIMA-1, is a Michael acceptor and prevents unfolding of wild-type P53 as well as mutant P53. Thus, it restores native wild-type conformation. “Various studies using solid tumour models have demonstrated MIRA-1induced P53-dependent endoplasmic stress and caspase-9-dependent apoptosis that confirms that anticancer activity of MIRA-1 is not only through mutant P53 but also via other molecular targets”. “MIRA-2 and MIRA-3 are structural analogues of MIRA-1 and inhibit cancer cell proliferation expressing P53R175H and P53R273H”. Besides, MIRA analogues increased DNA-binding ability of mutant P53 and enhanced expression of P53 target genes like MDM2 and CDKN1A in various cancer cells carrying mutant P53 protein. [175]
6 RITA R175H, R248W, R273H, R280K Thiophene derivative “RITA (reactivation of P53 and induction of tumour cell apoptosis), induces a conformational change resulting in the restoration of normal P53 function and activation of apoptosis in mutant P53”. “RITA inhibits tumour growth of renal cell carcinoma cells by causing DNA-protein cross-linking and upregulation of wild-type P53 and P21”. [176,177,178,179]
7 PK7088 Y220C Pyrazole PK7088 binds to the P53Y220C-specific surface cavity and stabilizes it while restoring wild-type P53 conformation. PK7088 targets cancer cells carrying the P53Y220C mutant and induces G2/M arrest of the cell cycle with increased expression of NOXA and CDKN1A. It also triggers the nuclear export of BAX into the mitochondria. [180]
8 PK11007 Y220C, V143A Sulfonylpyrimidine “PK11007 is a 2-sulfonylpyrimidine that binds to Cys182 and Cys277 in both wild-type P53 and the P53-Y220C mutant P53 and alkylate thiols via nucleophilic aromatic substitution resulting in P53 stabilization and restored P53-dependent activation of target genes like CDKN1A, PUMA and NOXA”. PK11007 anticancer activity is via both mutant-P53-dependent and mutant-P53-independent pathway, and like APR-246, PK11007 depletes GSH and increases the concentration of ROS in mutant P53-containing cancer cells. [181]
9 ZMC-1 (zinc metallochaperone-1) R175H, R172H (mouse) Thiosemicarbazone ZMC1 is a thiosemicarbazone derivative that displays selective toxicity towards cells carrying P53R175H, whereas it shows minimum toxic effect towards cells expressing wild-type P53 and other mutants of P53 like P53R248Q and P53R273H. “ZMC-1 displays mutant-P53 reactivation due to Zn2+ binding, which is essential for wild-type P53 structural stability”. “Administration of ZMC1 results in higher toxicity in P53R172H (which is equivalent to human P53R175H) mice than in wild-type P53 in a dose-dependent manner”. [17, 182]
10 COTI-2 R175H, Y220C, R248Q, I255N, R273H Thiosemicarbazone COTI-2 is a thiosemicarbazone-related compound that promotes the refolding of mutant P53 and restores wild-type-P53 function. The mechanism of action of COTI-2 is still unclear. COTI-2 displayed superior activity at Nanomolar concentrations than traditional chemotherapy or targeted-therapy agents against tumour cells, in vitro, and in vitro, as well as being safe and well-tolerated in vitro. COTI-2 showed activity against different types of human cancer lines regardless of their tissue of origin and genetic makeup. [183]
11 KSS-9 R175H, Piperlongumine KSS-9 and related C7-aryl piperlongumine derivatives displayed potent activity against human tumour cells. The cytotoxic activity, in particular, was more against the SKBR-3 breast cancer cells which carrying R175H mutation in P53 suppressor, and it also exhibited the ability to reactivate P53 mutation resulting in restoring of biological activity in SKBR3 cells. KSS-9-induced refolding of P53-R175H, and reactivation supplemented by increased expression of target genes like MDMD2, P21CIP1, and PUMA. Furthermore, KSS-9 induced abundant oxidative stress and actively disrupted the tubulin polymerization in vitro. [184]
12 P53R3 R175H, R273H, R248W, M273I Quinazoline The P53 reactivator (P53R3) compound identified in an in vitro DNA-binding assay. “It restores sequence-specific DNA binding of various P53 hot spot mutants (P53R175H, P53R248W, and P53273H) and increases the recruitment of wild-type P53 and P53M273I to several target genes, such as CDKN1A, GADD45, BAX, PUMA, PIG3 and MDM2. P53R3 also sensitizes glioma cells to apoptosis induced by TRAIL”. [185]
13 PEITC R175H Isothiocyanates Phenethyl isothiocyanate (PEITC) is a vegetable-derived compound that can reactivate the P53 mutant under in vitro and in vitro conditions. PEITC exhibits unusual antiproliferative activity against hotspot mutation P53R175H. From various mechanistic studies, it shows that PEITC induces apoptosis in a P53R175H mutant-dependent manner by restoring P53 wild-type conformation and transactivation. PEITC is a multifaceted compound that targets multiple pathways essential for the growth and development of cancer cells. The growth-inhibitory effects of PEITC is also due to increased ROS and depleted glutathione (GSH), leading to oxidative stress to kill the cancer cell. [186]
14 ReACP53 R175H, R248Q Peptide ReACP53 is a cell-penetrating peptide that rescues and increases the levels of functional and wild-type P53 protein in high-grade serous ovarian carcinomas (HGSOC) triggering cell cycle arrest and cell death. ReACP53 disrupts mutant-P53 aggregates and exhibited activity in ovarian cancer organoids and decreased intraperitoneal growth of OVCAR-3 ovarian cancer cells carrying mutant-P53in mice. “ReACP53 can also induce interaction of mutant-P53 with BAX with resulting mitochondrial cell death in castration-resistant prostate cancer (CRPC) cells”. [187, 188]
15 SCH529074 R175H, L194F, R248W, R249S, R273H Piperazinylquinazoline “SCH529074 is a small molecule that explicitly binds to the P53 DBD in a saturable manner”. “It acts as a chaperone and restores the PAb1620 epitope and increases the DBD activity of various P53 mutants”. This activity results in increased expression of multiple P53 target genes like CDKN1A, NOXA, BAX, cyclin G1, and PUMA. SCH529074 also inhibits wild-type P53 ubiquitination and degradation by MDM2. [189]
16 Stictic acid R175H, G245S 1,4-Dihydroxy-10-methoxy-5,8-dimethyl-3,7-dioxo-1,3-dihydro-7H-2,6,12-trioxabenzo [5, 6]cyclohepta[1,2-e]indene-11-carbaldehyde “Stictic acid is a natural product that binds to L1/S3 pocket with high-affinity in silico and thermostabilized P53-R175H and P53-G245S in vitro resulting in the restoration of wild-type P53 activity”. “Stictic acid also reactivated P53-R175H and P53-G245S mutants with the increases expression of P21 in a mutant-P53-dependent manner”. [190]
17 Chetomin R175H Epidithiodioxopiperazine “Chetomin (CTM) exhibits anticancer activity in vitro and in vivo in cells carrying P53R175H mutant with upregulation of MDM2, CDKN1A, and PUMA”. “CTM increases the interaction of heat shock protein 40 (HSP40) with P53R175H, resulting in restoring the wild-type P53 conformation”. [191]
18 PK083 Y220C Carbazole PhiKan083 (PK083) is a carbazole derivative that binds to and thermodynamically stabilizes P53-Y220C. PK083 causes mutant P53Y220C wild-type reactivation. [192]
19 RETRA R273H, R248Q, R280L, G266E Ethanone hydrobromide “Reactivate transcriptional activity (RETRA) increased β-galactosidase activity only in cancer cells carrying mutant P53 but also induced expression of P53 target genes. The increased β-galactosidase activity is absent in cells with wild-type or null P53. RETRA suppressed the growth of mouse tumour xenografts derived from human A431epidermal carcinoma cells expressing P53-R273H”. [193]