CRT0066101 . HCl

CRT0066101 is an inhibitor of all three PKD isoforms (IC50s = 1, 2.5, and 2 nM for PKD1, PKD2 and PKD3, respectively). It exhibits selectivity for PKD against a panel of >90 protein kinases, including PKCalpha, PKBalpha, MEK, ERK, c-Raf, c-Src and c-Abl. PKD family members play an important role in regulating several cellular processes and activities, including chromatin organization, Golgi function, gene expression, cell survival, adhesion, motility, differentiation, DNA synthesis and proliferation. CRT0066101 shows anticancer activity by blocking cell proliferation, inducing apoptosis, G2/M phase arrest, inhibiting migration and invasion and reducing the viability of several cancer cells both in vitro and in vivo. CRT0066101 reduced PKD-dependent NF-kappaB activation and NF-kappaB-dependent gene expressions in pancreatic cancer cells in vitro and showed antiviral activities inhibiting viral RNA replication and viral protein expression. Protein kinase D (PKD) has emerged as an important NLRP3 kinase that catalyzes the release of a phosphorylated NLRP3 species that is competent for inflammasome complex assembly. PKD inhibitor CRT0066101 could block NLRP3 inflammasome assembly and interleukin-1beta production. CRT0066101 also inhibits MyD88 and TLR4 expression and reduces NF-kappaB, ERK and JNK phosphorylation, indicating that it exerts anti-inflammatory effects on LPS-induced inflammation through the TLR4/MyD88 signaling pathway.