Novel DAG‐Lactone‐Based Vav1 Inhibitors Show Anti‐proliferative Activity in Pancreatic Cancer Models

Targeting C1 domains is a promising strategy for modulating the activity of signaling proteins driving tumor growth and progression. While most small molecules developed to date have focused on typical C1 domains, the development of regulators targeting atypical C1 domains remains under-explored. Herein, we describe the design and synthesis of novel cationic diacylglycerol DAG-lactones to efficiently interact with the negatively charged residues present in the atypical C1 domain of Vav1, a guanine nucleotide exchange factor playing a critical role in tumor development, including pancreatic cancer. We evaluated the therapeutic potential of this new family of compounds using models from this dismal condition where Vav1 is aberrantly expressed. Treatment of cultured pancreatic tumor cells with sn-1 cationic DAG-lactones inhibited proliferation of Vav1-expressing cells while Vav1-negative cells showed no response. Additionally, we demonstrated that these compounds inhibited growth of patient-derived organoids models of pancreatic cancer. These findings underscore the translational value of these cationic DAG-lactones for pancreatic cancer patients expressing Vav1 and serve as foundation for future approaches targeting atypical C1 domain-containing signaling proteins.