Chemical Variations on the p53 Reactivation Theme

Abstract

Among the tumor suppressor genes, p53 is one of the most studied. It is widely regarded as the "guardian of the genome", playing a major role in carcinogenesis. In fact, direct inactivation of the TP53 gene occurs in more than 50% of malignancies, and in tumors that retain wild-type p53 status, its function is usually inactivated by overexpression of negative regulators (e.g., MDM2 and MDMX). Hence, restoring p53 function in cancer cells represents a valuable anticancer approach. In this review, we will present an updated overview of the most relevant small molecules developed to restore p53 function in cancer cells through inhibition of the p53-MDMs interaction, or direct targeting of wild-type p53 or mutated p53. In addition, optimization approaches used for the development of small molecules that have entered clinical trials will be presented.

Keywords: MDM2 inhibitors; MDMX inhibitors; mutant p53; p53 activators; p53-MDM2 interaction inhibitors; p53-MDMX interaction inhibitors; small molecules; wild-type p53.

Figure 1

The p53-MDM2 interaction representation (PDB 1YCR). Phe19, Trp23 and Leu26 from a small amphipathic p53 derived α-helix (blue) are projected into the MDM2 pocket (grey surface).

Figure 2

Nutlin scaffold optimization and examples of nutlin derivatizations. Right upper quadrant: crystal structure of compound 3 bound to MDM2 (PDB 4IPF). MDM2 surface is colored in blue for hydrophilic areas and grey for hydrophobic areas. Compound 3 is depicted in stick model and is colored according to element type: white for carbon atoms, blue for nitrogen atoms, red for oxygen atoms, yellow for the sulfur atom, and green for chlorine atoms.

Figure 3

Benzodiazepinediones scaffold optimization. Right upper quadrant: crystal structure of compound 6 bound to MDM2 (PDB 1T4E). MDM2 surface is colored in blue for hydrophilic areas and grey for hydrophobic areas. Compound 6 is depicted in stick model and is colored according to element type: white for carbon atoms, blue for nitrogen atoms, red for oxygen atoms, dark red for the iodine atom, and green for chlorine atoms.

Figure 4

Examples of benzodiazepinedione derivatizations.

Figure 5

Isoindolinone scaffold optimization. Representations of binding modes were determined from chemical shift data and molecular docking [83,85].

Figure 6

Oxazoloisoindolinone derivative 18.

Figure 7

Chromenotriazolopyrimidine scaffold optimization. Right upper quadrant: crystal structure of compound 19 bound to MDM2 (PDB 3JZK). MDM2 surface is colored in blue for hydrophilic areas and grey for hydrophobic areas. Compound 19 is depicted as a stick model and is colored according to element type: white for carbon atoms, blue for the nitrogen atom, red for the oxygen atom, and dark red for bromine atoms.

Figure 8

Spiropyrrolidine scaffold optimization. Docking pose of compound 28 in MDM2 (PDB 3LBL). MDM2 surface is colored in blue for hydrophilic areas and grey for hydrophobic areas. Compound 28 is depicted in stick model and is colored according to element type: white for carbon atoms, blue for nitrogen atoms, red for oxygen atoms, bright green for fluorine, and dark green for chlorine atoms.

Figure 9

Spiropyrrolidines and others spiro-heterocyclic-oxindole derivatives.

Figure 10

Spiropyrrolidine, spirothiazolidine, and spirooxadiazoline oxindole derivatives with anti-cancer activity.

Figure 11

Indolyl derivatives. Right upper quadrant: structure of compound 41 bound to MDM2 (PDB 1YCR). MDM2 surface is colored in blue for hydrophilic areas and grey for hydrophobic areas. Compound 56 is depicted in stick model and is colored according to element type: white for carbon atoms, blue for nitrogen atoms, red for oxygen atoms, and green for chlorine atoms.

Figure 12

Pyrrolidine-2-carboxamide scaffold optimization. Right upper quadrant: crystal structure of compound 46 bound to MDM2 (PDB 4JRG). MDM2 surface is colored in blue for hydrophilic areas and grey for hydrophobic areas. Compound 46 is depicted in stick model and is colored according to element type: white for carbon atoms, blue for nitrogen atoms, red for oxygen atoms, and green for chlorine atoms.

Figure 13

Piperidinone scaffold optimization to AMG232.

Figure 14

Piperidinone and morpholinone derivatives. Right lower quadrant: crystal structure of compound 54 bound to MDM2 (PDB 4OAS). MDM2 surface is colored in blue for hydrophilic areas and grey for hydrophobic areas. Compound 54 is depicted in stick model and is colored according to element type: white for carbon atoms, blue for the nitrogen atom, red for oxygen atoms, yellow for the sulfur atom, and green for chlorine atoms.

Figure 15

p53-MDM2 interaction inhibitors.

Figure 16

MDMX and dual MDM2/MDMX inhibitors.

Figure 17

Compounds targeting mutant p53.