Acute Myeloid Leukemia (AML) accounts for a high percentage of all adult leukemia cases. Although most patients at first respond well to conventional chemotherapy, there is a high rate of relapse and patients become refractory to front-line treatment, which bears very poor prognoses and a five-year survival rate of only 14%. This application builds on our discovery of new highly selective kinase inhibitors that we want to develop as novel targeted anticancer compounds for the treatment of AML and later for other cancers as well. Kinase inhibitors represent a new class of anticancer drugs that can very specifically kill a cancer cell while having minimal effects on normal healthy tissues and organs because they target specifically molecules that are necessary for tumor cell growth. Development of such 'targeted drugs' is possible because of discoveries that have pinpointed the specific defects that cause certain cancers. In AML, the tyrosine kinase receptor FLT-3 is mutated and constitutively activated in up to 40% of patients. Inhibiting this mutant FLT-3 kinase now promises to be effective even as a mono therapy for these patients. We have identified a novel compound, GT-79 that binds with high affinity to FLT-3 wild type and mutant forms. GT-79 shows exceptional kinase selectivity when tested against 386 non-mutated kinases in a KinomeSCAN assay, which correlates with optimally targeted anticancer activity as established through testing in the NCI-60 screen. Importantly, our recent data demonstrate that GT-79 has excellent bioavailability, which suggests GT-79 as an outstanding new drug candidate for the treatment of AML. In this application we propose to 1) further characterize the kinase binding profile of GT-79, explore the growth inhibitory activity of GT-79 and analogs against FLT-3 mutant cell lines, and investigate the inhibition of FLT-3 kinase in vitro and in cell-based assays (Specific Aim 1); and to 2) investigate the anticancer efficacy of GT-79 in vivo using two AML xenograft models: MV4-11 and MOLM-13 cells; these animal experiments will also allow for a preliminary toxicity evaluation of GT-79 (Specific Aim 2). Establishing the efficacy and safety of GT-79 and further establishing its kinase binding profile and FLT-3 mutation dependence for its efficacy will place us in an optimal position to advance GT-79 into full preclinical and early clinical studies in a subsequent Phase II application. Once we have proven the efficacy of GT79 in AML xenografts, we will also evaluate GT-79 for the treatment of solid tumors, including GISTs, medullary thyroid cancer, and possibly certain renal cancers.
Public Health Relevance: The proposed studies are relevant to the development of novel FLT-3 inhibitors for the treatment of AML and other cancers. Kinase inhibitors have demonstrated effectiveness against a number of cancers where mutated kinases play a major role in cancerous cell growth. Successful examples of these so-called targeted anticancer drugs are Gleevec, Iressa, and more recently several other molecules. The discovery of FLT-3 mutations in nearly 40% of AML patients has identified FLT-3 as a promising target to develop novel targeted therapies for the treatment of AML. Unfortunately, most early FLT-3 inhibitors were not very selective or lacked sufficient bioavailability and have failed in the clinic due to sde effects and/or inefficacy. However some of these early compounds are still being evaluated as adjuvant therapies. One outstanding exception is a very selective high affinity compound (AC220) that has now shown promising results as mono therapy in a Phase II efficacy study. This demonstrates that highly selective kinase inhibitors can be successful in the clinic where less selective compounds often fail. We have identified a novel highly selective, high affinity FLT-3 inhibitor (GT-79) that shows excellent bioavailability in vivo. We propose to develop GT-79, which represents a unique chemical entity distinct from other FLT-3 inhibitors, as a new targeted treatment for AML and subsequently other cancers.
Public Health Relevance Statement: The proposed studies are relevant to the development of novel FLT-3 inhibitors for the treatment of AML and other cancers. Kinase inhibitors have demonstrated effectiveness against a number of cancers where mutated kinases play a major role in cancerous cell growth. Successful examples of these so-called targeted anticancer drugs are Gleevec, Iressa, and more recently several other molecules. The discovery of FLT-3 mutations in nearly 40% of AML patients has identified FLT-3 as a promising target to develop novel targeted therapies for the treatment of AML. Unfortunately, most early FLT-3 inhibitors were not very selective or lacked sufficient bioavailability and have failed in the clinic due to sde effects and/or inefficacy. However some of these early compounds are still being evaluated as adjuvant therapies. One outstanding exception is a very selective high affinity compound (AC220) that has now shown promising results as mono therapy in a Phase II efficacy study. This demonstrates that highly selective kinase inhibitors can be successful in the clinic where less selective compounds often fail. We have identified a novel highly selective, high affinity FLT-3 inhibitor (GT-79) that shows excellent bioavailability in vivo. We propose to develop GT-79, which represents a unique chemical entity distinct from other FLT-3 inhibitors, as a new targeted treatment for AML and subsequently other cancers.
NIH Spending Category: Biotechnology; Cancer; Childhood Leukemia; Hematology; Orphan Drug; Pediatric; Rare Diseases
Project Terms: Accounting; Adjuvant Therapy; adult leukemia; Adverse effects; Affinity; analog; Animal Experiments; Antibodies; anticancer activity; Antineoplastic Agents; base; Bcr-Abl tyrosine kinase; Binding (Molecular Function); Biochemical; Biological Assay; Biological Availability; Biological Process; cancer cell; Cancer Cell Growth; cancer therapy; cancer type; Cancerous; Carcinogenesis Inhibition; Cell Death; cell growth; Cell Line; Cell Proliferation; Cells; Characteristics; Chemicals; chemotherapy; Chronic Myeloid Leukemia; Clinic; Clinical; Clinical Research; Data; Defect; Dependence; Development; Disease; drug candidate; Drug Delivery Systems; drug development; Drug resistance; Effectiveness; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Evaluation; FDA approved; FLT3 gene; Gastrointestinal Neoplasms; Gefitinib; Generations; Gleevec; Goals; Growth; Human; Imatinib mesylate; In Vitro; in vivo; inhibitor/antagonist; interest; Killings; kinase inhibitor; Left; Leukemia, Myelocytic, Acute; Link; Malignant Neoplasms; medullary thyroid carcinoma; Mono-S; mutant; Mutate; Mutation; neoplastic cell; Nexavar; novel; Organ; outcome forecast; overexpression; Patients; PDGFRB gene; Pharmaceutical Preparations; Phase; phase 2 study; Phosphotransferases; Play; Positioning Attribute; pre-clinical; preclinical evaluation; preclinical study; Protein Kinase; protein kinase inhibitor; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Refractory; Relapse; Relative (related person); Renal carcinoma; Reporting; Research; research clinical testing; Resistance; Role; Safety; Signal Transduction; Signal Transduction Pathway; small molecule; Solid Neoplasm; Survival Rate; Sutent; Technology; Testing; Time; Tissues; Toxic effect; Ursidae Family; Xenograft Model; Xenograft procedure
