Design and Synthesis of Building Blocks for PPII‐Helix Secondary‐Structure Mimetics: A Stereoselective Entry to 4‐Substituted 5‐Vinylprolines

Chiha, Slim; Soicke, Arne; Barone, M.; Müller, Mat­thias; Bruns, Judith; Opitz, Robert; Neudörfl, Jörg‐Martin; Kühne, Ronald; Schmalz, Hans‐Günther

doi:10.1002/ejoc.201801732

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“…The compounds employed in this study were synthesized by modular assembly of the building blocks using established coupling protocols (40). The required ProM scaffolds ProM-1 (41, 43), ProM-2 (45), ProM-9 (46), ProM-13 (46), ProM-15 (47), and ProM-17 (47) (Fig. 1B) were synthesized as separately published.…”

Section: Resultsmentioning

confidence: 99%

“…For this reason the alkylated derivatives of ProM-1, i.e., ProM-9 and ProM-13 ( Fig. 1B), were synthesized (46) and used to prepare the desired inhibitors 6 and 7 (Table 1). Affinity measurements then showed that both inhibitors outperformed 1 substantially and lowered the K d to 380 nM (6) and 120 nM (7).…”

Section: Crystal Structures Of Enah Evh1 In Complex With Tedel-contaimentioning

confidence: 99%

“…In the course of our research into small molecules as potential inhibitors of protein-protein interactions (39) we recently in silico designed and stereo-selectively synthesized scaffolds, coined ProMs, which mimic pairs of prolines in PPII conformation (40). The modular combination of different ProMs thereby allowed us to generate nonpeptidic secondary-structure mimetics that fulfill the steric requirements of the addressed proline-rich motif-recognizing domain (41)(42)(43)(44)(45)(46)(47). For the EVH1 domain, our proof-of-concept study yielded a canonically binding, nontoxic,…”

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confidence: 99%

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Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells

Barone

Müller

Chiha

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Battling metastasis through inhibition of cell motility is considered a promising approach to support cancer therapies. In this context, Ena/VASP-depending signaling pathways, in particular interactions with their EVH1 domains, are promising targets for pharmaceutical intervention. However, protein–protein interactions involving proline-rich segments are notoriously difficult to address by small molecules. Hence, structure-based design efforts in combination with the chemical synthesis of additional molecular entities are required. Building on a previously developed nonpeptidic micromolar inhibitor, we determined 22 crystal structures of ENAH EVH1 in complex with inhibitors and rationally extended our library of conformationally defined proline-derived modules (ProMs) to succeed in developing a nanomolar inhibitor (Kd=120 nM,MW=734Da). In contrast to the previous inhibitor, the optimized compounds reduced extravasation of invasive breast cancer cells in a zebrafish model. This study represents an example of successful, structure-guided development of low molecular weight inhibitors specifically and selectively addressing a proline-rich sequence-recognizing domain that is characterized by a shallow epitope lacking defined binding pockets. The evolved high-affinity inhibitor may now serve as a tool in validating the basic therapeutic concept, i.e., the suppression of cancer metastasis by inhibiting a crucial protein–protein interaction involved in actin filament processing and cell migration.

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