PIN1degrader-3 is a degrader of Pin1 (peptidyl-prolyl isomerase protein) with an IC50 of 4.65 nM. It covalently binds to Pin1 and destabilizes it in vitro, leading to its degradation within cells. PIN1degrader-3 can be utilized in pancreatic cancer research.

Pin1:4.65 nM

PIN1 degrader-3 (Compound 164B8; Compound H-3-V) at a concentration of 250 μM for 3 hours binds to Pin1, causing a conformational change that affects the FG loop and D helix regions. At concentrations ranging from 0 to 15 μM over 24 hours, PIN1 degrader-3 effectively induces the dose-dependent degradation of MIA PaCa-2 and Pin1 in the human pancreatic cancer cell line BxPC3 and the mouse pancreatic cancer cell line KPC. When used at 5 μM for 24 hours, the induced degradation of Pin1 in BxPC3 and KPC cell lines is reversible. Furthermore, PIN1 degrader-3 at concentrations between 0.5 and 10 μM over 24 hours triggers dose-dependent degradation of Pin1 in all cancer-associated fibroblasts (CAFs) including CAF-BTG from cholangiocarcinoma, CAF-APP from appendiceal cancer, and CAF-COL from colorectal cancer. PIN1 degrader-3 treatment for 72 hours reduces cell viability, with an EC50 value of 8.4 μM in MIA PaCa-2 cells and 5.3 μM in KPC cell lines.

The compound known as PIN1 degrader-3 (Compound 164B8; Compound H-3-V), administered at 30-60 mg/kg via intraperitoneal injection once daily for five days a week over two weeks, effectively inhibits the growth of KPC cell allograft tumors and directly leads to the degradation of Pin1 in tumor tissue. However, high doses may cause hematologic toxicity.