The emergence of therapy resistance and adaptation in acute myeloid leukemia (AML) remains a major challenge, leading to treatment failure and mortality. We and others have provided experimental evidence supporting novel idea that adaptation and resistance to therapy could be in early stages driven by signaling pathway rewiring, rather than genetic mutations. This project aims to advance our novel GAB1 inhibitors, targeting the adaptor protein GAB1- a key regulator of multiple signaling pathways implicated in therapy resistance. Within our past ERC StG grant “Signaling Propensity in the Microenvironment of B Cell Chronic Lymphocytic Leukemia” (2019–24), we demonstrated that GAB1 inhibition is effective as a single agent and also counteracts resistance in various hematologic malignancies, including highly aggressive AML (our US patent 11,648,255B2). Inhibiting GAB1 is particularly challenging due to its role as a docking protein, requiring innovative drug design distinct from conventional kinase inhibitors. This PoC project has five key objectives: (i) develop and patent a 2nd-generation GAB1 inhibitors, (ii) establish robust biochemical and biological assays for therapeutic evaluation, (iii) identify malignancies responsive to GAB1 inhibition and generate preclinical in vitro and in vivo data, (iv) elucidate GAB1-mediated signaling modulation in cancer, and (v) assess market potential, formulate a business plan, and secure industry partnerships. Successful execution will enable further preclinical development of this docking protein inhibitor and facilitate clinical translation of our lead compound.