Table 2.

Small molecules with proposed mutant p53 corrector activity

Compounds	Proposed mechanism/comments	Refs
Antimonials	Deliver antimony, which binds noncovalently to the cysteine triad (C124–C135–C141) to structurally stabilize temperature-sensitive p53 mutants.	[4]
APR-246/PRIMA-1	Prodrug with the active compound being MQ. MQ binds covalently to several cysteine residues in p53 and thermodynamically stabilizes p53 mutants. Off-target thiol reactivity may contribute to anticancer activity.	[70]
ATO	Delivers arsenic, which binds covalently to the cysteine triad (C124–C135–C141) to structurally stabilize structural p53 mutants.	[3]
Chetomin	Restores activity of p53R175H mutants. Binds Hsp40 and increases Hsp40/p53R175H interaction to restore wild-type-like conformation.	[95]
COTI-2	Thiosemicarbazone that binds p53 in vitro and induces a wild-type-like conformation in p53R175H mutants.	[96]
CP-31398	first identified putative mutant p53 reactivator. Antitumor activity was later attributed to off-target activities. The compound reacts with thiols.	[53,54]
KG13	Covalently binds to C220 in p53Y220C mutants and improves structural stability. Selective for p53Y220C mutants.	[61]
MANIO	Activates wild-type and mutant p53. Binds to the p53 core domain and induces thermal stabilization.	[52]
MB710, MB725	Bind to the Y220C-induced surface crevice and structurally stabilize p53Y220C mutants. Selective for p53Y220 mutants.	[59]
MIRA-1	Stabilizes a wild-type like conformation of p53 mutants and induces DNA-binding. It is a maleimide derivative and reacts with thiols and amines. Antiproliferative effect may be due to off-target activity.	[97]
P53R3	Induces DNA binding of p53 mutants in vitro and preferentially inhibits growth of TP53 mutant cell lines.	[98]
PC14586	Clinical compound that binds to the Y220C-induced surface crevice and structurally stabilizes p53Y220C mutants. Selective for p53Y220 mutants.	[6]
Phenethyl isothiocyanate	Natural compound that restores wild-type-like conformation to p53R175H. Depletes glutathione and activity is blocked by antioxidants. Mode of action may be indirect.	[99]
PhiKan083 (PK083)	The first small molecule targeting the Y220-mutation-induced surface crevice. Structurally stabilizes p53Y220C mutants. Selective for p53Y220 mutants.	[55]
PK11007	One of several sulfonylpyrimidine-derived thiol-reactive agents that lead to thermal stabilization of p53 mutants. Preferentially targets cystine residues in p53.	[100]
PK5196	Binds to the Y220C-induced surface crevice and structurally stabilizes p53Y220C mutants. Selective for p53Y220 mutants.
PK7088	Binds to the Y220C-induced surface crevice and structurally stabilizes p53Y220C mutants. Selective for p53Y220 mutants.	[58]
PK9328	Improved Y220 pocket binder. Based on PhiKan083. Selective for p53Y220 mutants.	[101]
SLMP53-1	Activates wild-type and mutant p53 by inducing thermal stabilization.	[102]
Stictic acid	Natural compound that was selected as a L1/S3 pocket binder. Induces thermal stabilization of pSS02453 and p53R175H mutants in vitro.	[71]
STIMA-1	Enhances DNA binding of mutant p53 and induces p53-dependent gene expression. Compound shows thiol reactivity, and antiproliferative effects may be due to off-target activity.	[103]
UCI-LC0019/LC0023	Binds noncovalently to the L1/S3 pocket. Induces sequence-specific DNA binding of p53R175H mutants in vitro.	[5]
ZMC1 (NSC319726)	Thiosemicarbazone that acts as zinc chaperone to structurally stabilize p53 mutants with reduced zinc-binding potential.	[81]