Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors

Abstract

Mouse double minute 2 homolog (MDM2, Hdm2) is an important negative regulator of the tumor suppressor p53. Using a mRNA based display technique to screen a library of >1012 in...

Biochemical and Structural Characterization of a Peptidic Inhibitor of the YAP:TEAD Interaction That Binds to the α-Helix Pocket on TEAD

“…To identify peptides that bind to human TEAD4 (region 217–434), we used the RNA-display technology (10 12 in-vitro translated macrocyclic peptides) as previously described . The mRNA display screening revealed a macrocyclic hit series with several strongly enriched analogues (Table S1).…”

Synthesis and Mechanism of p53‐MDM2 Inhibitors with Heterocyclic Structures: A Focused Review

“…The 2‐position of the indole ring is oxidized to a carbonyl group; the 3‐position is a spiro atom, and the substituted pyrrole ring shares the same carbon atom; the 7‐position of the indole ring is often substituted (usually chlorinated). X ‐ray diffraction analysis shows that the indole ring or the structure similar to the indole ring has a good combination with the active cavity of Trp23, and the substituted tetrahydropyrrole ring has a hydrophobic effect with the active cavity of Phe19 and Leu26 [38] . The effects of spiroepoxyindole compounds are more significant.…”

“…In addition, the research data in vivo also showed that spirooxyindole compounds were active compounds with excellent pharmaceutical properties for oral use. In particular, APG‐115 has a very high affinity for MDM2 (Ki<1 nM), strong cell activity and good oral pharmacokinetic characteristics, and can achieve complete and lasting tumor regression in vivo [38] …”

“…X-ray diffraction analysis shows that the indole ring or the structure similar to the indole ring has a good combination with the active cavity of Trp23, and the substituted tetrahydropyrrole ring has a hydrophobic effect with the active cavity of Phe19 and Leu26. [38] The effects of spiroepoxyindole compounds are more significant. So Nutlins and spiroepoxyindole derivatives are considered to be two types of efficient and selective p53-MDM2 inhibitors with cell membrane permeability.…”

“…In particular, APG-115 has a very high affinity for MDM2 (Ki < 1 nM), strong cell activity and good oral pharmacokinetic characteristics, and can achieve complete and lasting tumor regression in vivo. [38] The structure-activity relationship of spirooxyindole is shown in Figure 7. Many compounds have entered clinical studies, such as APG-115 and DS-3032b (Figure 3, compound 34).…”