Reviving the guardian of the genome: Small molecule activators of p53

Abstract

The tumor suppressor p53 is one of the most important proteins for protection of genomic stability and cancer prevention. Cancers often inactivate it by either mutating its gene or disabling its function. Thus, activating p53 becomes an attractive approach for the development of molecule-based anti-cancer therapy. The past decade and half have witnessed tremendous progress in this area. This essay offers readers with a grand review on this progress with updated information about small molecule activators of p53 either still at bench work or in clinical trials.

Keywords: Drug discovery; Inauhzin; MDM2; MDMX; Small molecules; p53.

Figure 1. MDM2/MDMX Inhibitors

MDM2:p53, MDMX:p53, and dual MDM2/MDMX:p53 antagonists primarily function as protein:protein inhibitors, disrupting the interaction between the N-terminal transactivating domain of p53 and the N-terminal p53-binding domains of its principle regulators MDM2 and MDMX. MDM2 inhibitors function by directly inhibiting MDM2 activity. Both JNJ-26854165 and HLI98 bind to MDM2's RING finger domain; JNJ-26854165 blocks proteasome interaction with MDM2:p53 complex and HLI98 inhibits MDM2 ubiquitin ligase activity. SP-141 binds to the N-terminal p53-binding domain through an undetermined mechanism destabilizes MDM2.

Figure 2. Mutant-to-wild type p53 converting activators

ZMC1 is a zinc ionophore and chelator that provides the R175H mutant enough zinc in its local environment to overcome its reduced affinity for Zn²⁺ and induce wild-type folding. PK7088 binds to a cleft present in the Y220C mutant, increasing its thermal stability and promoting wild-type folding. Chemotin (CTM) first binds to heat shock protein 40kD (Hsp40), which forms a complex with p53-R175H and through an undefined mechanism promotes wild-type conformational change. P53R3 and SCH529074 bind to p53's DNA binding domain (DBD) and through an undefined mechanism function in a chaperone-like manner to induce wild-type folding of multiple forms of p53 mutants. APR-246 is metabolized to methylene quinuclidinone (MQ), which forms adducts with cysteine residues in p53's DBD, promoting and stabilizing wild-type conformation.

Figure 3. Indirect p53 activators

Tenovin-6 inhibits both sirtuin 1 (SirT1) and sirtuin 2 (SirT2) deacetylases, but with higher affinity for SirT1, while AEM1 selectively inhibits SirT2. Inhibition of SirT1/SirT2 promotes the acetylation of p53, simultaneously enhancing site-specific DNA binding while protecting it from MDM2-mediated ubiquitination. Inauhzin targets both SirT1 and IMP dehydrogenase 2 (IMPDH2). Inhibition of IMPDH2 causes a decrease in cellular GTP levels and subsequent destabilization of nucleostemin (NS) protein. The resultant induction of ribosomal stress frees ribosomal protein L5 (RPL5) and ribosomal protein L11 (RPL11) from ribosomes, allowing them to bind MDM2, protecting p53 from MDM2

Figure 4. Inhibitors of Mutant p53's Gain of Function

RETRA, NSC59984, and prodigiosin reverse mutant p53 gain-of-function (GOF) inhibition of tumor suppressor and family member p73. APR-246 metabolite methylene quinuclidinone (MQ) also forms adducts with thioredoxin reductase 1 (TrxR1) and glutathione (GSH), generating reactive oxygen spieces (ROS) and serves as a second mechanism of action.