Here, we report the synthesis and preliminary characterization of IODVA1, a novel and potent small molecule that is active in xenograft mouse models of breast and Ras-driven lung cancers. In an effort to inhibit oncogenic Ras signaling, we conducted an in silico screen against a Ras conformation that mimics the structure of nucleotide-free Ras in complex with Sos (Ford et al., 2005 & 2009; Soisson et al., 2001). Top scoring candidates identified in the in silico search were screened for inhibition of proliferation of A549 and H292 lung cancer cells and inhibition of colony formation of NIH-3T3 cells expressing RasG12V. NSC124205, a NCI/DTP Open Chemicals Repository molecule, was among the top candidates that fulfilled both criteria. Biochemical analysis showed that even though NSC124205 is potent on several cell lines harboring active Ras, its mechanism of action is Ras-independent. Mass spectroscopy analysis revealed that NSC124205 was a mixture of at least three compounds. Attempts to identify and synthesize the active ingredient in NSC-124205 yielded IODVA1. IODVA1 decreased proliferation and actin polymerization and filopodia formation in MDA-MB-231. Compared to vehicle treated, tumors of breast cancer MDA-MB-231 and lung cancer H2122 cells xenograft mice significantly decreased when treated with IODVA1. Immuno-histochemistry analysis of tumor sections suggests that cell death occurs by increased apoptosis. Therefore, IODVA1 holds promise as a therapeutic agent to inhibit tumor growth.

IODVA1, a di-pyridine derivative with <i>in vivo</i> activity against cancer models

2019 Fall National Meeting

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IODVA1, a di-pyridine derivative with in vivo activity against cancer models