Aim: The immunosuppressive drug brequinar (BQR) is a potent inhibitor of dihydroorotate dehydrogenase (DHODH) active against autoimmune diseases and viral infections. This oral drug is currently evaluated for the treatment of cancers, notably acute myeloid leukemia to limit the suppressive function of myeloid cells. A combination of BQR and an anti-PD-1 (programmed death-1) antibody has revealed potent antitumor and antimetastatic activities. BQR induced a marked down-regulation of PD-L1 (programmed death-ligand 1) gene expression and a large decrease of PD-L1 protein expression in implanted tumors in mice. Methods: The present study evaluated the capacity of BQR to interact directly with the PD-L1 protein dimer using molecular modeling. Results: Molecular docking experiments revealed a modest capacity of BQR to stabilize PD-L1 dimers. The PD-L1 binding capacities of four known BQR analogs were compared to establish structure-binding relationships. The protein binding was significantly enhanced when the acid function of BQR was replaced with a trifluoroethanol substituent. The interaction was further reinforced when BQR was coupled to a mitochondria-targeted triphenylphosphine (TPP) unit. Among three BQR-TPP hybrids, compound B2 with a short alkyl linker revealed a prominent capacity to interact with PD-L1, superior to that of the reference biphenyl ligand BMS-202. Conclusions: Two PD-L1 binders derived from BQR have been identified and the protein interaction modeled. Our study underlines the possibility of designing novel small molecule ligands targeted to the PD-L1 dimer interface based on the BQR scaffold.

Traditional medicines and their active ingredients and some natural products and derived analogs have been used for treating multiple diseases including cancer. Among these compounds cytotoxic agents such as bleomycin, paclitaxel and vincristine block essential pathways and genes required for cancer cell growth and these agents have diverse clinical applications. Dietary phenolics including flavonoids and related compounds are associated with multiple health benefits however most individual dietary compounds and other natural products that show promising anticancer activity in preclinical studies exhibit minimal clinical effectiveness and this is particularly true for cancer. Many of the compounds perform poorly in clinical trials due to pharmacokinetic consideration and limited uptake (e.g., curcumin) and these are issues that can be addressed. The clinical effectiveness of flavonoids and many other natural product-derived anticancer compounds can also be enhanced by a more targeted approach. This would include identifying a significant response/gene or target in a specific cancer and then identifying the optimal compound. In this review, I have discussed a limited number of targets including non-oncogene addiction genes such as Sp transcription factors, reactive oxygen species (ROS) or the orphan nuclear receptor 4A (NR4A) sub-family. Thus, the most active compound for these responses could be used only for treating patients that are ROS-inducible or highly express targets such as Sp1 or NR4A sub-family members. A mechanism-based precision medicine approach should enhance the clinical efficacy of dietary and related natural products as anticancer agents and decrease toxic side effects for some combination therapies.

Protein-protein interactions (PPIs) impersonate a significant role in many biological processes and are potential therapeutic targets in numerous human diseases. Stapled peptides, as the most promising therapeutic candidate for interfering with PPIs, have a higher degree of α-helicity, improved binding affinity, more resistance to proteolytic digestion, longer serum half-life, and enhanced cell permeability, which exhibits higher pharmacological activity compared with small molecule drugs and biologics. This review outlined the continuous progress of stapled peptides mainly concerning the design principle, structural stability, bioactivity, cell permeability, and potential applications in therapeutics, which is aimed at providing a broad reference for the design and exploration of stapled peptides with enhanced biological and pharmacokinetic properties as the next-generation therapeutic peptide drugs targeting various diseases.