812 Indolium 1 exerts activity against vemurafenib-resistant melanoma in vivo

The development of targeted therapies (Braf/MEK inhibitors) and immunotherapy have had a major impact on the treatment melanoma. However, majority patients with advanced melanoma succumb to their disease. mechanisms resistance both immunotherapies are numerous been well described. These include alternative activation Braf/MEK signaling, novel compensating mutations in additional oncogenes, loss neoantigens. Thus, there is an urgent need for melanomas utilizing action. We previously identified triphenylmethanes as class which shows activity against wide variety tumors. synthesized triphenylmethane, indolium 1, demonstrated its efficacy aggressive vemurafenib-resistant vivo. ATAC Seq analysis tumors treated Indolium 1 vs vehicle revealed mechanism action induces tumor suppressor EphA3 Surprisingly, also downregulates expression Rb gene vitro vivo, providing biomarker activity. While has long thought be gene, amplified human melanoma, thus suggesting that it may oncogenic well. Moreover, required Ras-mediated transformation. Our findings extend requirement transformation Braf provide initial description small molecule completely different than existing therapies. believe pre-IND studies warranted this compound given ability inhibit growth