A Novel Synthetic Smoothened Antagonist Transiently Inhibits Pancreatic Adenocarcinoma Xenografts in a Mouse Model

Hedgehog (Hh) signaling is over-activated in several solid tumors where it plays a central role in cell growth, stroma recruitment and tumor progression. In the Hh signaling pathway, the Smoothened (SMO) receptor comprises a primary drug target with experimental small molecule SMO antagonists currently being evaluated in clinical trials.Using Shh-Light II (Shh-L2) and alkaline phosphatase (AP) based screening formats on a "focused diversity" library we identified a novel small molecule inhibitor of the Hh pathway, MS-0022 (2-bromo-N-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)benzamide). MS-0022 showed effective Hh signaling pathway inhibition at the level of SMO in the low nM range, and Hh pathway inhibition downstream of Suppressor of fused (SUFU) in the low µM range. MS-0022 reduced growth in the tumor cell lines PANC-1, SUIT-2, PC-3 and FEMX in vitro. MS-0022 treatment led to a transient delay of tumor growth that correlated with a reduction of stromal Gli1 levels in SUIT-2 xenografts in vivo.We document the in vitro and in vivo efficacy and bioavailability of a novel small molecule SMO antagonist, MS-0022. Although MS-0022 primarily interferes with Hh signaling at the level of SMO, it also has a downstream inhibitory effect and leads to a stronger reduction of growth in several tumor cell lines when compared to related SMO antagonists

3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3‑<i>b</i>]pyridine-5-carbonitriles Are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase‑3

Plasmodium falciparum is the infective agent responsible for malaria tropica. The glycogen synthase kinase-3 of the parasite (<i>Pf</i>GSK-3) was suggested as a potential biological target for novel antimalarial drugs. Starting from hit structures identified in a high-throughput screening campaign, 3,6-diamino-4-(2-halophenyl)-2-benzoylthieno­[2,3-<i>b</i>]­pyridine-5-carbonitriles were discovered as a new class of <i>Pf</i>GSK-3 inhibitors. Being less active on GSK-3 homologues of other species, the title compounds showed selectivity in favor of <i>Pf</i>GSK-3. Taking into account the X-ray structure of a related molecule in complex with human GSK-3 (<i>Hs</i>GSK-3), a model was computed for the comparison of inhibitor complexes with the plasmodial and human enzymes. It was found that subtle differences in the ATP-binding pockets are responsible for the observed <i>Pf</i>GSK-3 vs <i>Hs</i>GSK-3 selectivity. Representatives of the title compound class exhibited micromolar IC₅₀ values against P. falciparum erythrocyte stage parasites. These results suggest that inhibitors of <i>Pf</i>GSK-3 could be developed as potential antimalarial drugs