Table 1.

Overview of mutant-p53 targeting and wild-type p53 activating agents.

Compound/Peptide/Antibody			Chemical Name and/or Class	Target/Mechanism	Clinical Development	References
Targeting wild p53 activation	p53 activator	RITA		Binds to p53 and prevents WT p53 degradation by blocking interaction with MDM2	Experimental and/or preclinical	[78]
	MDM2 inhbitors	Nutlin-3a	Cis-imidazoline	Blocks the interactive binding sites of p53 and MDM2, dramatically increasing the half-life of p53 and activating p53-mediated transcription.	The listed inhibitors, except nutlin-3a, have undergone or are currently undergoing clinical trials	[9,79]
		RG7112	Cis-imidazoline
		RG7388	Cis-imidazoline
		RG7775	Pegylated prodrug idasanutlin
		MI-77301	Spirooxindole
		AMG232	Piperidinone
		SAR405838	Piperidinone
		MK-8242	2(1H)-Pyrimidinone
		CGM097	Dihydroisoquinolinone
		DS-3032b	Unknown
		HDM201	Imidazopyrrolidinone
	MDM2/MDMX(MDM4) dual inhibitors	ALRN-6924	Stapled peptide	Blocks the interactive binding sites of p53 and MDM2/MDMX(MDM4), dramatically increasing the half-life of p53 and activating p53-mediated transcription.	currently undergoing clinical trials
		RO-5963 RO-2443	indolyl hydantoin	Binds to MDMX(MDM4)/MDM2 and blocks p53-MDM2/MDMX interaction		[32]
	MDM2 degradators	PROTAC 8, A1874	IMiD-based MDM2	Targeted degradation of MDM2 using proteolysis targeting chimeras (PROTACs)	Experimental and/or preclinical	[9,80]
	Gene therapy- based on oncolytic Viruses	ONYX-015	Recombinant adenovirus with wild-type p53 (Ad-p53)	A mutant adenovirus with a deleted E1B-55Kd gene commonly fails to replicate efficiently in cells with a wild-type p53 but replicates in many (but not all) cells with a mutant p53 gene.	In clinical trials	[9,81,82]
		Gendicine (Ad-53)	Recombinant adenovirus engineered to express wildtype-p53 (rAd-p53)	Gene replacement (gene therapy)	Approved in 2003 by the China Food and Drug Administration (CFDA) to treat head and neck cancer	[9,83,84]
Targeting mutant p53	Restoration of wild-type function to mutant p53	CP-31398	Styrylquinazoline	Cysteine-binding compounds, Michael acceptor binding to mutant p53	Experimental and/or preclinical	[85]
		PRIMA-1	Quinuclidinone	Cysteine-binding compound is converted to MQ, which binds mutant p53 by Michael addition	Experimental and/or preclinical	[86]
		APR-246	Quinuclidinone	Cysteine-binding compound is converted to MQ, which binds mutant p53 by Michael addition	Phase Ib/II for ovarian cancer, MDS, and oesophageal cancer	[87]
		MIRA-1	Maleimide	Michael acceptor binding to mutant p53	Experimental and/or preclinical	[88]
		STIMA-1	Styrylquinazoline	Michael acceptor binding to mutant p53	Experimental and/or preclinical	[89]
		3-Benzoylacrylic acid	Benzoylacrylate	Binds to mutant p53 by Michael addition	Experimental and/or preclinical	[90]
		KSS-9	Piperlongumine	Microtubule poison; redox; Michael acceptor binding to mutant p53	Experimental and/or preclinical	[91]
		PK11007	Sulfonylpyrimidine	Binds to mutant p53 by nucleophilic aromatic substitution	Experimental and/or preclinical	[92]
		ZMC1 ZMC2 ZMC3 ZN-1	Thiosemicarbazone	Zn2+ chelator	Experimental and/or preclinical	[48]
		COTI-2	Thiosemicarbazone	Zn2+ chelator	Phase I for gynecological tumors and head and neck cancer	[93]
		SLM P53-1	Tryptophanol-derived oxazoloisoindolinone	restores wt-like DNA binding ability to mut p53R280K Bridges extra interaction between p53 and DNA that rescues DNA binding and transcription activity	Experimental and/or preclinical	[94,95]
		SLM p53-2	Tryptopha-nol-derived oxa-zoloisoindolinone	Restores wild-type-like conformation and DNA-binding ability, possibly by enhancing interaction with Hsp70.	Experimental and/or preclinical	[96]
		MB725 MB710	Aminobenzothiazole	Binds to Y220C of p53 DBD	Experimental and/or preclinical	[46]
		PK083 Pk9318	Carbazole	Binds to Y220C of p53 DBD		[44,45]
		pCAPs	Peptides	Binds to mutant p53 and promotes refolding	Experimental and/or preclinical	[97]
	Mutant p53 degradation	Ganetespib Onalespib Luminespib TAS-116		Depletion of mutant p53 using HSP90 inhibitors or statins	In clinical trials	[9,98]
		Vorinostat	Suberanilohydroxamic acid (SAHA)	Histone deacetylase (HDAC) inhibitor, destabilizes mut p53 through inhibition of the HDAC6-HSP90 chaperone axis, and at the same time, inhibit the transcription of mutant p53 through HDAC8	In clinical trials	[72,77,99,100]
		Atorvastatin Lovastatin		Statin drugs, Inhibition of mevalonate pathway	In clinical trials	[9,101]
		NSC59984		Activation of MDM2		[21]
		Spaurtin		Chaperone-mediated autophagy (CMA) pathway		[102]
		Reacp53	Peptide	Disrupts mutant-p53 aggregates	Experimental and/or preclinical	[8]
	Interruption of mutant GOF	RETRA	2-(4,5-Dihydro-1,3-thiazol-2-ylthio)-1-(3,4-dihydroxyphenyl) ethanone	Binds to mutant p53 and disrupts mutant-p53–p73 complexes	Experimental and/or preclinical	[103]
		Prodigiosin		Disrupts mutant-p53–p73 complexes	Experimental and/or preclinical	[22]
	Immunotherapy	H2-scDb H2-Fab	Bispecific antibody	Bispecific antibody links T cells to cancer cells with one arm binding to T cell receptor and the other arm binding to HLA-mutant p53 R175H peptide on cancer cell surface.	Experimental and/or preclinical	[104]

Abbreviations: HSP40, heat shock protein 40; MDS, myelodysplastic syndrome; MQ, methylene quinuclidinone; p73, tumor suppressor protein p73 (p53 family member). Data partially reviewed from references [9,10,77,105,106].