In vivo modulation of hypoxia-inducible signaling by topographical helix mimetics

Abstract

Development of small-molecule inhibitors of protein-protein interactions is a fundamental challenge at the interface of chemistry and cancer biology. Successful methods for design of protein-protein interaction inhibitors include computational and experimental high-throughput and fragment-based screening strategies to locate small-molecule fragments that bind protein surfaces. An alternative rational design approach seeks to mimic the orientation and disposition of critical binding residues at protein interfaces. We describe the design, synthesis, biochemical, and in vivo evaluation of a small-molecule scaffold that captures the topography of α-helices. We designed mimics of a key α-helical domain at the interface of hypoxia-inducible factor 1α and p300 to develop inhibitors of hypoxia-inducible signaling. The hypoxia-inducible factor/ p300 interaction regulates the transcription of key genes, whose expression contributes to angiogenesis, metastasis, and altered energy metabolism in cancer. The designed compounds target the desired protein with high affinity and in a predetermined manner, with the optimal ligand providing effective reduction of tumor burden in experimental animal models.helix mimics | hypoxia signaling | synthetic inhibitors of transcription

Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality

“…For example, Lao et al designed an α-helical mimetic of the HIF1a transactivation domain that binds to the cysteine-histidine rich 1 (CH1) domain on CBP/p300. The optimized compound OHM1 is based on a bis-oxopiperazine scaffold; OHM1 binds CH1 with a Kd = 500 nM (Table 1), down-regulates hypoxia inducible genes, and inhibits tumor growth in a xenograft model (Lao et al, 2014). Computational approaches to systematically replace peptide residues have also seen some promising success (Guo et al, 2014).…”

Synthesis and screening of small-molecule α-helix mimetic libraries targeting protein–protein interactions

“…After removal of Nosyl protecting group, coupling of another triazine derivative to resin-bound piperazines 18 followed by cleavage reaction generated trifunctionalized triazine-piperazine-triazines 20 in excellent yield (the average purity of crude final product was over 92%). Arora and co-workers have described a solid-phase methodology to prepare oxopiperazine helix mimetics [24 ] by modifying a solution-phase synthetic method [63] previously developed by the same group (Figure 3e). After loading two amino acid residues on resin using Fmoc chemistry, N-terminus was protected with Nosyl group to afford 21.…”

Non-covalent S⋯O interactions control conformation in a scaffold that disrupts islet amyloid polypeptide fibrillation

“…This increases the population of the desired conformer and thus reduces the entropic cost of binding. Previous non-peptidic scaffolds have taken advantage of hydrogen bonding, 12–16 the stereoelectronic preferences of secondary aryl amides, 13,17,18 steric repulsion between vicinal cyclic systems, 19,20 dipolar repulsion, 21,22 cyclisation, 23 and metal templation 24 to provide conformational pre-organisation (Fig. 1).…”