Structure-based discovery of novel α-aminoketone derivatives as dual p53-MDM2/MDMX inhibitors for the treatment of cancer

Discovery of JN122, a Spiroindoline-Containing Molecule that Inhibits MDM2/p53 Protein–Protein Interaction and Exerts Robust In Vivo Antitumor Efficacy

“…Upon HPLC purification, a TFA salt of 59h was obtained as a white solid (15 mg, 20%). (59,JN18). Method D: 59h (15 mg, 0.03 mmol), K 2 CO 3 (17 mg, 0.12 mmol), and LiOH•H 2 O (13 mg, 0.3 mmol) were used.…”

“…For examples, potent MDM2 inhibitors, Nutlin-3a ( 7 ) and 8 (Figure ), also blocked MDM4/p53 interaction with relatively weaker activities. 9 , 10 , 11 , 12 , 13 , 14 , and others , were reported as dual inhibitors that efficiently block MDM2/p53 and MDM4/p53 interaction with nanomolar IC 50 values. ALRN-6924 is a highly potent, peptide-based dual inhibitor of MDM2 and MDM4 that exhibited superior activities in cancer cells overexpressing MDM4 compared to selective MDM2 inhibitors, suggesting dual inhibitors might be better than the selective ones. , Encouragingly, ALRN-6924 has progressed into phase II human clinical trials for the treatment of advanced or metastatic solid tumors with wild-type p53 and pediatric cancer. , Despite these recent advancements, small-molecule dual inhibitors of MDM2/4 with robust in vivo efficacy are still few.…”

“…48 For examples, potent MDM2 inhibitors, Nutlin-3a (7) 19 and 8 39 (Figure 1), also blocked MDM4/p53 interaction with relatively weaker activities. 9, 54 10, 39 11, 55 12, 56 13, 57 14, 58 and others 59,60 were reported as dual inhibitors that efficiently block MDM2/p53 and MDM4/ p53 interaction with nanomolar IC 50 values. ALRN-6924 is a highly potent, peptide-based dual inhibitor of MDM2 and MDM4 that exhibited superior activities in cancer cells overexpressing MDM4 compared to selective MDM2 inhibitors, suggesting dual inhibitors might be better than the selective ones.…”

“…1 H NMR (400 MHz, Methanol-d 4 ): δ 8.26 (d, J = 8.3 Hz, 1H), 7.73−7.57 (m, 3H), 7.44 (t, J = 7.5 Hz, 1H), 7.40−7.22 (m, 4H), 7.16 (d, J = 13.4 Hz, 1H), 4.63 (d, J = 9.9 Hz, 1H), 4.54 (d, J = 7.6 Hz, 1H), 4.18 (d, J = 9.1 Hz, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 3.63 (d, J = 14.5 Hz, 1H), 3.61− 3.49 (m, 1H), 3.39 (d, J = 14.5 Hz, 1H), 3.20−3.07 (m, 1H), 2.07 (dd, J = 14.8, 10.3 Hz, 1H), 1.51 (d, J = 14.9 Hz, 1H), 1.24 (t, J = 7.0 Hz, 3H), 1.14 (s, 9H). LRMS (ESI) calculated for C 34 H 41 Cl 2 FN 3 O 4 [M + H] + = 644.2; obtained: 644.3.4-((2′S,3S,4′S,5′R)-6-Chloro-4′-(2-chlorophenyl)-1′-ethyl-2′neopentylspiro[indoline-3,3′-pyrrolidine]-5′-carboxamido)-3-methoxybenzoic Acid(59, JN18). Method D: 59h (15 mg, 0.03 mmol), K 2 CO 3 (17 mg, 0.12 mmol), and LiOH•H 2 O (13 mg, 0.3 mmol) were used.…”

Novel 9-Methylanthracene Derivatives as p53 Activators for the Treatment of Glioblastoma Multiforme

“…Therefore, reducing MDM4 or MDM2 expression and restoring p53 function represent an attractive GBM treatment strategy. Various MDM intracellular protein-protein interaction inhibitors have been developed to stabilize p53 for cancer treatment [18,19]. Although several MDM2 inhibitors have entered clinical trials, increasing evidence suggests that enhanced inhibition of MDM4 remains critical for this class of inhibitors to exert more sensitive and potent activity to release p53 [20].…”