Targeting Mutant p53 for Cancer Treatment: Moving Closer to Clinical Use?

Abstract

Mutant p53 is one of the most attractive targets for new anti-cancer drugs. Although traditionally regarded as difficult to drug, several new strategies have recently become available for targeting the mutant protein. One of the most promising of these involves the use of low molecular weight compounds that promote refolding and reactivation of mutant p53 to its wild-type form. Several such reactivating drugs are currently undergoing evaluation in clinical trials, including eprenetapopt (APR-246), COTI-2, arsenic trioxide and PC14586. Of these, the most clinically advanced for targeting mutant p53 is eprenetapopt which has completed phase I, II and III clinical trials, the latter in patients with mutant TP53 myelodysplastic syndrome. Although no data on clinical efficacy are currently available for eprenetapopt, preliminary results suggest that the drug is relatively well tolerated. Other strategies for targeting mutant p53 that have progressed to clinical trials involve the use of drugs promoting degradation of the mutant protein and exploiting the mutant protein for the development of anti-cancer vaccines. With all of these ongoing trials, we should soon know if targeting mutant p53 can be used for cancer treatment. If any of these trials show clinical efficacy, it may be a transformative development for the treatment of patients with cancer since mutant p53 is so prevalent in this disease.

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

“…Amplification of N-myc is a key oncogenic driver and prognostic indicator in NB. , As such, NB cells without N-myc amplification (i.e., SH-SY5Y cells: 2–3 N-myc copies , ) were compared to those with N-myc amplification [i.e., BE(2)-C cells; 120–500 N-myc copies , ] in terms of the ability of the PPP4pT series to inhibit proliferation after a 24- and 72 h incubation (Table ). The PPP4pT series were compared to a panel of control ligands, including DFO, ,, the clinically trialed thiosemicarbazones, Triapine , and COTI-2, − and the lead compounds from our previous three series of thiosemicarbazones, namely, Dp44mT, DpC, and PPP44mT. ,, …”

Targeting Biomolecular Condensation and Protein Aggregation against Cancer

“…379 Several candidates have been found to interact with Y220C p53, causing conformational changes and reactivating p53 functionalities. 380 384 APR-246 and its derivatives are Michael acceptors reacting with cysteines and mediating correct folding and apoptosis in mutant p53 cancer cells. 385,386 It has completed phase I, II, and III CTs, the latter combined with azacitidine in patients with mutant p53 MDS.…”

“…Because the mutation creates a surface cleft, the region became a suitable target for developing novel molecules . Several candidates have been found to interact with Y220C p53, causing conformational changes and reactivating p53 functionalities . These lead compounds are often Michael acceptors reacting by alkylation with cysteines 124 and 277.…”

Gain of Function (GOF) Mutant p53 in Cancer—Current Therapeutic Approaches

“…Recently a study using such technology reported new genes ( GPSM2, OR4N2, CTSL2, SPERT, RPE65 ) that may be associated with p53 functions, which seem to be a better fit for the platinum-based therapies for patients than their TP53 status [ 104 ]. The ongoing discussion between researchers on whether personal therapy, which considers the investigation of molecules targeting the exact type of mutation of TP53 , should be pursued or not has yet to be unraveled [ 105 , 106 , 107 , 108 , 109 ].…”