Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment

Abstract

Design of small-molecule inhibitors (MDM2 inhibitors) to block the MDM2-p53 protein-protein interaction has been pursued as a new cancer therapeutic strategy. In recent years, potent, selective, and efficacious MDM2 inhibitors have been successfully obtained and seven such compounds have been advanced into early phase clinical trials for the treatment of human cancers. Here, we review the design, synthesis, properties, preclinical, and clinical studies of these clinical-stage MDM2 inhibitors.

Figure 1

Inhibition of p53 by MDM2 and MDMX.

Figure 2

MDM2 (surface)–p53 (green line and sticks) complex.

Figure 3

Nutlins and their analogs.

Figure 4

Cocrystal structure of 2 and MDM2. The p53 peptide is green.

Figure 5

Superposition of cocrystal structures of MDM2 to 3 (cyan) and 1 (orange).

Scheme 1. Synthesis of 3

Reagents and reaction conditions: (a) AlMe₃, toluene, reflux; (b) phosgene, Et₃N; (c) Et₃N; (d) resolution by chiral chromatography.

Figure 6

MDM2 binding of pyrrolidine-containing MDM2 inhibitors.

Figure 7

Cocrystal structure of MDM2 and 4.

Scheme 2. Synthesis of 6

Reagents and reaction conditions: (a) AgF, Et₃N, CH₂Cl₂, rt, 18 h; (b) CF₃CO₂H, CH₂Cl₂, rt, 18 h; (c) Resolution by chiral chromatography; (d) Ph₂POCl, (i-Pr)₂NEt, CH₂Cl₂, rt; (e) aq NaOH, THF, methanol, 40 °C.

Figure 8

Structures and MDM2 binding of spiro-oxindole-containing compounds.

Figure 9

X-ray cocrystal structure of MDM2/10.

Scheme 3. Synthesis of 10

Reagents and reaction conditions: (a) toluene, molecular sieves 4 Å, reflux overnight; (b) trans-4-aminohexanol, THF, rt, 2 days; (c) CAN, acetonitrile–H₂O–acetone, ice bath, 5 min; (d) methanol–H₂O, rt, 1–4 days.

Figure 10

Structures of piperidinone-containing compounds.

Figure 11

NMR structure of MDM2/11 (left) and X-ray crystal structures of MDM2/11 analogue (middle and right).

Figure 12

X-ray cocrystal structure of MDM2/13 (cyan).

Scheme 4. Synthesis of 14

Reagents and reaction conditions: (a) 10% t-BuOK, THF, rt, 2 d; (b) 0.2% RuCl₂[(S-xylBINAP)(S-DAIPEN)], 40% t-BuOK, i-PrOH, H₂ (50 PSI), rt, 65 h; (c) LiOH, THF/MeOH/H₂O; (d) PPTS, toluene, reflux; (e) LiHMDS, allyl bromide, THF; (f) neat, 100 °C, overnight; (g) Tf₂O, 2,6-lutidine, CH₂Cl₂, −78 to 0 °C; (h) aq NaHCO₃; (i) Tf₂O, 2,6-lutidine. (j) Method A: i-PrSNa, DMF. Method B: i-PrSO₂Na, acetonitrile. Method C: i-PrSH, base, DMF. (k) RuCl₃, NaIO₄, acetonitrile/CCl₄/H₂O.

Figure 13

Examples of reported MDM2 inhibitors in the literature.