Musechem

RG7388(cas 1229705-06-9) is an oral, selective, small molecule MDM2 antagonist that inhibits binding of MDM2 to p53. RG7388 binds to MDM2 blocking the interaction between the MDM2 protein and the transcriptional activation domain of the tumor suppressor protein p53. By preventing the MDM2-p53 interaction, p53 is not enzymatically degraded and the transcriptional activity of p53 is restored. This may lead to p53-mediated induction of tumor cell apoptosis.

Kinases can switch between active and inactive conformations of the ATP/Mg(2+) binding motif DFG, which has been explored for the development of type I or type II inhibitors. However, factors modulating DFG conformations remain poorly understood. We chose CDK2 as a model system to study the DFG in-out transition on a target that was thought to have an inaccessible DFG-out conformation. We used site-directed mutagenesis of key residues identified in structural comparisons in conjunction with biochemical and biophysical characterization of the generated mutants. As a result, we identified key residues that facilitate the DFG-out movement, facilitating binding of type II inhibitors. However, surprisingly, we also found that wild type CDK2 is able to bind type II inhibitors. Using protein crystallography structural analysis of the CDK2 complex with an aminopyrimidine-phenyl urea inhibitor ( K03861 ) revealed a canonical type II binding mode and the first available type II inhibitor CDK2 co...

Favipiravir (cas 259793-96-9 ), also known as T-705 or Avigan, is an antiviral drug that selectively inhibits the RNA-dependent RNA polymerase of influenza virus. It is phosphoribosylated by cellular enzymes to its active form, favipiravir-ribofuranosyl-5'-triphosphate (RTP). Favipiravir is active against a broad range of influenza viruses, including A(H1N1)pdm09, A(H5N1) and the recently emerged A(H7N9) avian virus. It also inhibits influenza strains resistant to current antiviral drugs, and shows a synergistic effect in combination with oseltamivir, thereby expanding influenza treatment options.

ACP-105(cas 899821-23-9) is a non-steroidal selective androgen receptor modulator used in the treatment of Alzheimer’s.

BLU-285(cas 1703793-34-3) is a potent and selective inhibitor of PDGFRα D842V and KIT Exon 17 mutants and is being developed as a highly targeted therapy for SM, a disorder of the mast cells in which a KIT Exon 17 mutation is the primary driver of disease. BLU-285 has demonstrated biochemical in vitro activity on the KIT exon 17 mutant enzyme, KIT D816V (half-maximal inhibitory concentration [IC50] = 0.27 nM). In vivo BLU-285 was well tolerated and has demonstrated dose dependent antitumor efficacy. Complete tumor growth inhibition and ≥ 75% KIT kinase inhibition was observed with 10 mg/kg once daily, oral dosing of BLU-285 in the aggressive KIT exon 17 mutant driven P815 mastocytoma model grown as a solid tumor allograft as well as in a disseminated model of disease. BLU-285 is currently in Phase I clinical study.

Elafibranor (cas 923978-27-2) is an agonist of the peroxisome proliferator-activated receptor-α (PPAR-α) and peroxisome proliferator-activated receptor-δ (PPAR-δ) with EC50 values of 45 and 175 nM, respectively. Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation. We assessed the safety and efficacy of elafibranor in an international, randomized, double-blind placebo-controlled trial of patients wit h nonalcoholic steatohepatitis (NASH).

Tis108 is a triazole-type strigolactone (SL)-biosynthesis inhibitor that reduces the level of 2'-epi-5-deoxystrigol (epi-5DS) in rice. Treatment of TIS108 increased the number of branches and repressed root hair elongation as was observed in SL-deficient mutants, and co-application of GR24, a synthetic SL analog, rec overed the TIS108-induced phenotype to that of wild-type.