IODVA1, a guanidinobenzimidazole derivative, targets Rac activity and Ras-driven cancer models

Abstract

We report the synthesis and preliminary characterization of IODVA1, a potent small molecule that is active in xenograft mouse models of Ras-driven lung and breast cancers. In an effort to inhibit oncogenic Ras signaling, we combined in silico screening with inhibition of proliferation and colony formation of Ras-driven cells. NSC124205 fulfilled all criteria. HPLC analysis revealed that NSC124205 was a mixture of at least three compounds, from which IODVA1 was determined to be the active component. IODVA1 decreased 2D and 3D cell proliferation, cell spreading and ruffle and lamellipodia formation through downregulation of Rac activity. IODVA1 significantly impaired xenograft tumor growth of Ras-driven cancer cells with no observable toxicity. Immuno-histochemistry analysis of tumor sections suggests that cell death occurs by increased apoptosis. Our data suggest that IODVA1 targets Rac signaling to induce death of Ras-transformed cells. Therefore, IODVA1 holds promise as an anti-tumor therapeutic agent. OPEN ACCESS Citation: Gasilina A, Premnauth G, Gurjar P, Biesiada J, Hegde S, Milewski D, et al. (2020) IODVA1, a guanidinobenzimidazole derivative, targets Rac activity and Ras-driven cancer models. PLoS ONE 15(3): e0229801. https://doi.org/ 10.

Inhibition of the RacGEF VAV3 by the small molecule IODVA1 impedes RAC signaling and overcomes resistance to tyrosine kinase inhibition in acute lymphoblastic leukemia

“…S1A–D ). Together, these results indicate that IODVA1 specifically targets proliferation and survival of BCR-ABL1-transformed cells and are consistent with our previous report that IODVA1 targets transformed cells [ 11 ].

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“…IODVA1 is specific to RAC (IC50 = 1 μM) and is less effective on CDC42 and not at all on RHOA (Supplementary Fig. S4A, B ), consistent with our previous observations in MDA-MB-231 cells [ 11 ]. As a result of decrease in activation of RAC, phosphorylation levels of downstream signaling molecules were decreased—JNK by 1.8-fold ( p = 0.004), S6 by 1.5 ( p = 0.046), 4EBP by 3.0 ( p = 0.001), and PAK by 6.1 ( p = 0.0005) fold, respectively.…”

“…We have reported that IODVA1 has no inhibitory activity in vitro against major wild-type kinases including ABL1 and SRC-like kinases [ 11 ]. We confirmed that it does not target BCR-ABL1 by immuno-precipitating it from p190-BCR-ABL1-Ba/F3 cells treated with vehicle control, imatinib, or IODVA1 (3 μM) and probing its phosphotyrosine levels by immunoblotting.…”

“…6B ). One can argue that IODVA1 inhibits BCR-ABL1 or the transmembrane or cytosolic protein tyrosine kinases responsible for VAV3 phosphorylation [ 33 ]; however, this is unlikely since IODVA1 is not a kinase inhibitor [ 11 ] and BCR-ABL1 phosphorylation levels or activity are not affected by IODVA1 (Supplementary Fig. S2 ).…”

“…We recently identified the small molecule IODVA1, a 2-guanidinobenzimidazole derivative with anti-tumorigenic properties. Initial characterization of IODVA1 ruled out kinase inhibition potential but showed inhibition of RAC activity and signaling at low concentrations and within minutes of exposure [ 11 ]. Here, we use in vitro and in vivo leukemic models of the chimeric BCR-ABL1 oncoprotein B-cell acute lymphoblastic leukemia (Ph + B-ALL) and Ph-like to reveal the mechanism of action of IODVA1.…”