Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction

Abstract

Intrinsically disordered proteins are an emerging class of proteins without a folded structure and currently disorder-based drug targeting remains a challenge. p53 is the principal regulator of cell division and growth whereas MDM2 consists its main negative regulator. The MDM2-p53 recognition is a dynamic and multistage process that amongst other, employs the dissociation of a transient α-helical N-terminal "lid" segment of MDM2 from the proximity of the p53complementary interface. Several small molecule inhibitors have been reported to inhibit the formation of the p53-MDM2 complex with the vast majority mimicking the p53 residues Phe19, Trp23 and Leu26. Recently, we have described the transit from the 3-point to 4-point pharmacophore model stabilizing this intrinsically disordered N-terminus by increasing the binding affinity by a factor of 3. Therefore, we performed a thorough SAR analysis, including chiral separation of key compound which was evaluated by FP and 2D NMR. Finally, p53-specific anti-cancer activity towards p53-wild-type cancer cells was observed for several representative compounds.

Optimized Inhibitors of MDM2 via an Attempted Protein‐Templated Reductive Amination

“…Amine 23 ( K i =3.18±0.18 μ m ) is almost six‐fold less potent than aldehyde 3 . Interestingly, 18 ( K i =0.63±0.07 μ m ) is three times more potent than its regioisomer in which the CH 2 −NH is reversed ( K i =1.9 μ m ) . Surprisingly, compound 22 shows a K i value of 0.095±0.010 μ m , which makes it by far the most potent inhibitor of this series.…”

“…Interestingly, 18 (K i = 0.63 � 0.07 μm) is three times more potent than its regioisomer in which the CH 2 À NH is reversed (K i = 1.9 μm). [28] Surprisingly, compound 22 shows a K i value of 0.095 � 0.010 μm, which makes it by far the most potent inhibitor of this series. In fact, the compound is almost as potent against MDM2 as Nutlin-3 (K i = 0.036 � 0.009 μm [44] ).…”

“…Some time ago, we found the Leu26 pocket to be a flexible pocket, which is enlarged upon ligand binding (four‐point pharmacophore model) . Very recently, we expanded this work with a thorough SAR analysis . The flexibility of the pocket makes it very difficult to target using structure‐based drug design (SBDD) or other computational techniques such as virtual screening.…”

“…[27] Very recently, we expanded this work with a thorough SAR analysis. [28] The flexibility of the pocket makes it very difficult to target using structure-based drug design (SBDD) or other computational techniques such as virtual screening. Therefore, KTGS holds the potential to explore this flexible binding pocket by letting the protein select which combination of building blocks ideally fits.…”

Multicomponent Peptide Stapling as a Diversity‐Driven Tool for the Development of Inhibitors of Protein–Protein Interactions

“…[27][28][29] Thes tructure of the complex exhibits helical conformation, [30] whereas this domain in free Nterminal domain of p53 is natively unfolded. [31,32] Fort hat reason, peptide stapling is nowadays recognized as an effective approach to produce a-helical peptides mimicking the p53 transactivation domain. [23,[33][34][35] By targeting the dual inhibition of p53-MDM2 and MDMX interactions as validated targets,w ea im to demonstrate the potential of Ugi multicomponent macrocyclizations in the rapid discovery [36] of peptide inhibitors of proteinprotein interactions (PPIs).…”