PDS-0330 (PDS0330) is a first-generation, specific small molecule claudin-1 inhibitor with Kd of 22.9 uM in MST binding assays, impairs the interaction between claudin1 and pSrc/Src and alters survival signaling pathways.
PDS-0330 shows no significant affinity against human claudin-19 and mouse claudin-4, which have 56% and 47% sequence identity to claudin-1.
PDS-0330 inhibits claudin1-mediated signaling by interfering with its binding to Src, reduces anoikis resistance and therapy/chemoresistance.
PDS-0330 inhibits claudin-1 -mediated invasive and tumorigenic effects, causes an increase in apoptosis as evidenced by an increase in apoptotic protein cleaved PARP while a decrease in anti-apoptotic proteins including Bcl2, Bcl-xL, and Survivin in claudin-1 expressing SW480cld1 and SW620 cells.
PDS-0330 inhibits cell viability of SW480cld1 cells and SW620 cells with EC50 of 8.4 and 9.3 uM, respectively, with no effect on cell growth/survival in claudin-1 deficient HCT116 cells.
PDS-0330 exhibits favorable absorption, distribution, metabolism and excretion (ADME) and Pharmacokinetics.
PDS-0330 (5 mg/kg and 10 mg/kg) inhibits xenograft tumor formation by claudin-1 overexpressed SW480cld1 and SW620 cells without showing cytotoxicity.
Claudin-1 is one of 27 claudin family members, Claudin-1 has been found to be overexpressed in primary CRC and metastasis, as well as in CRC cell lines.
Claudin-1 has also been shown to play a role in Wnt and Notch signaling which contribute to cancer progression and metastasis.