Abstract A103: Developing small molecules to disrupt IL-17RB and MLK4 interaction for pancreatic cancer treatment

Abstract

Abstract Nearly 40% of pancreatic cancer overexpressed pro-inflammatory Interleukin-17 receptor B (IL-17RB), and this signal pathway plays an essential role in promoting tumorigenesis and metastasis. Targeting the initial event of IL-17B/IL-17RB oncogenic signaling by disrupting IL-17RB-MLK4 interaction represents an excellent strategy for treating pancreatic cancer. To develop specific and effective small molecule disruptors, we have established a high-throughput screening (HTS) method using pY447 IL-17RB signal-based assay to identify blockers inhibiting IL-17B/IL-17RB oncogenic signaling. Three FDA-approved drugs were found to inhibit IL-17B-induced pY447 of IL-17RB signaling after screening 2560 FDA-approved drugs and 11000 TKI-related compounds. These drugs are more effective than the original loop peptide in inhibiting soft agar colony formation and spheroid formation of pancreatic tumor cells. Furthermore, we identified Drug H, which was not an anticancer drug before, could efficiently and specifically disrupt the interaction between IL-17RB and MLK4. Oral administration of Drug H can significantly suppress pancreatic tumor growth and metastasis and extend the life of mice with pancreatic tumors. Combining Drug H with gemcitabine treatment also showed synergistic effects in suppressing pancreatic tumor growth and metastasis. These data suggest Drug H may be a promising lead compound for disrupting IL-17RB/MLK4 and treating pancreatic cancer. Citation Format: I-Chih Chen, Yi-Ling Ko, Ching-Hsuan Huang, Jiin-Horng Lee, Yung-Cheng Lo, Chun-Mei Hu. Developing small molecules to disrupt IL-17RB and MLK4 interaction for pancreatic cancer treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A103.