Discovery, Synthesis, and Biological Evaluation of Orally Active Pyrrolidone Derivatives as Novel Inhibitors of p53–MDM2 Protein–Protein Interaction

Abstract

The p53-MDM2 interaction has been proved to be a valuable target to develop effective antitumor agents. Novel p53-MDM2 inhibitors bearing pyrrolidone scaffolds were successfully identified by structure-based design. The nanomolar inhibitor 5 possessed good p53-MDM2 inhibitory activity (K(i) = 780 nM) due to its hydrophobic and hydrogen bonding interactions with MDM2. Further hit optimization led to the discovery of a number of highly potent pyrrolidone derivatives with improved p53-MDM2 inhibitory activity and in vitro antiproliferative potency. Compounds 41 (K(i) = 260.0 nM) and 60a (K(i) = 150.0 nM) showed good and selective activity against tumor cells with deleted p53. In addition, these two compounds also effectively inhibited the tumor growth in the A549 xenograft model. Interestingly, compound 41 was proved to be a potent MDM2/MDMX dual inhibitor. The novel pyrrolidone p53-MDM2 inhibitors represent promising lead structures for the development of novel antitumor agents.

Organocatalytic, Diastereo- and Enantioselective Synthesis of Nonsymmetric cis-Stilbene Diamines: A Platform for the Preparation of Single-Enantiomer cis-Imidazolines for Protein–Protein Inhibition

“…4 These small molecules have received much attention from academia and industry in the past decade, since the function of wild-type (WT) p53 is inactivated by overexpression 5 or amplification 6 of MDM2, even though the p53 gene is either deleted or mutated in approximately 50% of all human cancers. 7−9 Additionally, since MDM2 is overexpressed in many types of cancer and functions as a key negative regulator of wild-type p53, the Nutlins have shown promise as anticancer therapeutics. Hoffmann-La Roche (HLR) was the first to advance a Nutlin analogue (RG7112) into clinical trials for solid and hematological tumors.…”

Rapid identification of dual p53-MDM2/MDMX interaction inhibitors through virtual screening and hit-based substructure search

“…RO-2443 forms two H-bonds with Gln72A, whereas NSC148171 only forms one H-bond with Gln72A. This may explain the difference in activity between RO-2443 (IC 50 ¼ 33 nM) 26 and NSC148171 (K i ¼ 620 nM) ( Fig. 5A and B).…”

“…While RO-2443 and RO-5963 share the same skeleton, K23, WW8, 4t and nutlin-3 possess similar pharmacophores. Second, several crystal structures of some of these compounds in complex with MDM2 and/or MDMX have been reported, 25,26 showing two different binding modes of MDM2/MDMX at the inhibitor-protein interface. MDM2 differs in binding mode between its complexes with RO-2443 (PDB CODE: 3VBG) and K23 (PDB CODE: 3LBK), whereas MDMX shows a difference in binding between its complexes with RO-2443 (PDB CODE: 3U15) and WW8 (PDB CODE: 3LBJ).…”

Reviving the guardian of the genome: Small molecule activators of p53

“…Structure-based design has also led to the development of several other molecules that target MDM2's hydrophobic cleft using various chemical scaffolds, such as methylbenzo-amines (Dudgeon et al, 2010), imidazole-indoles (Czarna et al, 2010), isoindolinones (Hardcastle et al, 2006; Hardcastle et al, 2011; Riedinger et al, 2011), pyrrolopyrimidines (Lee et al, 2011), sulphonamides (Galatin & Abraham, 2004), and benzodiazepines (Z. Yu et al, 2014; Zhuang et al, 2011), which all demonstrate nanomolar binding affinities to MDM2 and with one pyrrolidinone exhibiting dual MDM2/MDMX activity (Zhuang et al, 2012) and one pyrrolopyrazole seemingly active against both MDM2 and the NF-κB complex (Zhuang et al, 2014), a different cancer-related pathway (DiDonato, Mercurio, & Karin, 2012). Perhaps most promising are a series of piperidonones (AM-8553, AM-7209, AMG 232) and morpholinones (AM-8735) developed from Amgen laboratories that exhibit exceptional pharmacokinetic properties, such as low clearance rate, long half-life, and high oral bioavailability (Gonzalez-Lopez de Turiso et al, 2013; Gonzalez, Eksterowicz, et al, 2014; Rew et al, 2012; Rew et al, 2014; Sun et al, 2014).…”