78P Small molecule compounds targeting the p53 mutants

The tumor suppressor p53 is inactivated by mutation in about half of all tumors, making mutant a prime target for cancer therapy. Missense mutations R248W, R273H and R248Q are included the five most frequent total lead to more than 630 000 new diagnosed cases diseases world every year. These mutations, located at or near protein-DNA interface, inactivation loss direct p53-DNA interactions, causing conformational changes protein, resulting lowering its stability. Using small molecule drugs reactivate promising therapeutic approach treating wide variety human malignancies. aim this research was study biological properties derivatives aminobenzothiazole considered as selective small-molecule stabilizers p53(R248W), p53(R273H) p53(R248Q) mutants. Mutant recombinant proteins were expressed E. coli BL21 (DE3) pLysS purified using affinity size exclusion chromatography. Determination compounds performed surface plasmon resonance (SPR) isothermal titration calorimetry (ITC). cytotoxicity assessed on cell lines containing MTS test. activity studied cytofluorimetric analysis cycle programmed death, quantitative real-time PCR expression p53-dependent genes, immunoblotting intracellular protein level changes. Derivatives found stabilize mutants lines, reactivating transcriptional production proteins. p53-mutated p53-wild type cells. studies will provide detailed understanding molecular mechanisms reactivation various forms p53, which, turn, decisive importance development personalized anticancer drugs. funded RSF grant 22-24-20034 strategically supported Kazan Federal University Strategic Academic Leadership Program (PRIORITY-2030).