SBIR-STTR Award

Inhibition of tyrosine kinase activity has been identified as an approach to develop new anti-cancer drugs. Several drugs that target tyrosine kinases are now marketed in the United States and many more kinase directed drugs are in clinical trials for cancer. Directing anti-cancer therapies at discrete molecular targets that are more important for the growth or survival of cancer cells than normal cells, such as particular protein kinases, offers the potential to develop effective drugs with far less severe side effects than are observed with most current anti-cancer drugs. A proprietary, modular, structure-based drug design approach has been used to construct a library of small molecules that bind to the peptide-binding site on pp60c-src (Src), a tyrosine kinase that affects multiple pathways involved in tumorigenesis. An initial 269 compound library was screened for growth inhibition in KM12 colon and H460 lung cancer cell lines and more than 90 active compounds were identified that comprise several diverse structural classes. Compounds with nanomolar in vitro potency for inhibiting the growth of these cancer cells were selected for further development. Preliminary efficacy in mouse xenograft models has been demonstrated. Structure-activity relationship studies have provided data that were used to generate two successive probe libraries. These analogs have improved solubility and in several cases improved potency, in cells. The goal of the studies proposed in this application is to select a compound for full pre-clinical development, following the evaluation of pharmacokinetic properties and in vivo efficacy. The studies proposed in this application are relevant to public health because we propose to develop a new class of anti-cancer drugs that have the potential to be very effective in stopping cancer growth as well as preventing the spread of cancer to other organs. Because of the nature of these drugs, we expect them to be much less toxic than drugs that are currently available to cancer patients. Cancer represents a large unmet medical need in the United States and research such as that proposed in this application addresses this need.

Thesaurus Terms:
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KX2-391 is a new cancer drug that is in Phase 1 clinical trials and was discovered and is being developed by Kinex Pharmaceuticals (Applicant). During the Phase 1 trial, plasma, white blood cells (PBMC's) and tumor biopsy tissue will be collected. These clinical samples will eventually be evaluated for KX2-391 related biomarkers which will provide tools to monitor the efficacy of the drug and to potentially identify patients who are most likely to benefit from this treatment. In addition, these biomarkers will be helpful in designing Phase 2 and Phase 3 clinical trials, and monitoring their success. The experiments proposed in this grant application are focused on identifying and validating KX2-391 associated biomarkers by first using mouse models for various human cancers such as colon, pancreas, prostate and breast. KX2-391 has been shown to be efficacious in mouse models for these types of cancer and these types of cancer are being considered for Phase 2 clinical trials. Once potential biomarkers are identified in the animal studies, they will be used to analyze human samples. The goal of biomarker research is to identify genes or proteins that can be used to detect disease, monitor progress to a therapy, monitor treatment compliance, determine treatment efficacy, predict response to treatment and to stage disease. These goals are certainly ambitious; however the potential payoff would be tremendous. Funding research to provide these benefits to patients is clearly warranted.

Public Health Relevance:
The research that is proposed in this grant application will support the further development of a novel cancer drug that has been shown to inhibit both primary tumor growth and metastasis. The drug is currently in Phase 1 clinical trials where safety and pharmacokinetics are being evaluated as primary endpoints. Tissue samples from patients in the Phase 1 trial are being procured for the development of biomarker tests to measure drug efficacy and to identify potential patient populations who are sensitive to this drug.

Public Health Relevance Statement:
Project Narrative The research that is proposed in this grant application will support the further development of a novel cancer drug that has been shown to inhibit both primary tumor growth and metastasis. The drug is currently in Phase 1 clinical trials where safety and pharmacokinetics are being evaluated as primary endpoints. Tissue samples from patients in the Phase 1 trial are being procured for the development of biomarker tests to measure drug efficacy and to identify potential patient populations who are sensitive to this drug.

Project Terms:
(Z)-2-[4(1,2-diphenyl-1-butenyl)-phenoxyl]-N,N-dimethylethanamine; 1,2-diaminocyclohexane platinum oxalate; 1,2-diamminocyclohexane(trans-1)oxolatoplatinum(II); 1-(2-Oxo-4-amino-1,2-dihydropyrimidin-1-yl)-2-deoxy-2,2-difluororibose; 1-OHP; 1-p-beta-dimethylamino-ethoxyphenyl-trans-1,2-diphenylbut-1-ene; 2',2'-DFDC; 2',2'-difluoro-2'-deoxycytidine; 2',2'-difluorodeoxycytidine; 2'-deoxy-2'-difluorocytidine; 2'Deoxy-2',2'-Difluorocytidine; 2,2 difluorodexoycytidine; Animal Model; Animal Models and Related Studies; Animals; Anti-Cancer Agents; Anti-Tumor Agents; Anti-Tumor Drugs; Antineoplastic Agents; Antineoplastic Drugs; Antineoplastics; Antiproliferative Agents; Antiproliferative Drugs; Applications Grants; Biopsy; Biopsy Sample; Biopsy Specimen; Blood Plasma; Blood leukocyte; Body Tissues; Breast; Breast Cancer Cell; Cancer Drug; Cancer Patient; Cancer cell line; Cancer, Oncology; Cancers; Canine Species; Canis familiaris; Chemotherapeutic Agents, Neoplastic Disease; Clinical; Clinical Trials; Clinical Trials Design; Clinical Trials, Phase I; Clinical Trials, Phase II; Clinical Trials, Phase III; Clinical Trials, Unspecified; Cola; Colon Cancer; Colon Carcinoma; Colonic Carcinoma; Common Rat Strains; Compliance behavior; Data; Development; Diaminocyclohexane Oxalatoplatinum; Difluorodeoxycytidine; Disease; Disorder; Dogs; Dose; Drug Combinations; Drug Kinetics; Drugs; Drugs, Investigational; Early-Stage Clinical Trials; Ethanamine, 2-(4-(1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl-, (Z)-; Evaluation; Funding; Gastrointestinal Tract, Pancreas; Genes; Genital System, Male, Prostate; Genus Cola; Goals; Grant Proposals; Grants, Applications; Hand; Heterograft; Human; Human Breast Cancer Cell; Human Prostate; Human Prostate Gland; Human, General; In Vitro; Investigational Drugs; Investigational New Drugs; L-OHP cpd; LC/MS; Leukocytes; Link; MCF-7; MCF-7 Cell; MCF7; MCF7 cell; Malignant Neoplasms; Malignant Pancreatic Neoplasm; Malignant Tumor; Malignant neoplasm of pancreas; Mammals, Dogs; Mammals, Mice; Mammals, Rats; Mammals, Rodents; Man (Taxonomy); Man, Modern; Marrow leukocyte; Measures; Medication; Metastasis; Metastasize; Metastatic Neoplasm; Metastatic Tumor; Mice; Monitor; Murine; Mus; Neoplasm Metastasis; Oxalatoplatin; Oxalatoplatinum; Pancreas; Pancreas Cancer; Pancreatic; Pancreatic Cancer; Patient Compliance; Patient Cooperation; Patients; Peptides; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacodynamics; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Phase; Phase 1 Clinical Trials; Phase 2 Clinical Trials; Phase 3 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phase II Clinical Trials; Phase III Clinical Trials; Plasma; Position; Positioning Attribute; Pre-Clinical Model; Preclinical Models; Primary Neoplasm; Primary Tumor; Prostate; Prostate Gland; Prostatic Gland; Protein-Tyrosine Kinases, src; Proteins; Rat; Rattus; Research; Reticuloendothelial System, Leukocytes; Reticuloendothelial System, Serum, Plasma; Rodent; Rodentia; Rodentias; SBIR; SBIRS (R43/44); SCID; SCID Mice; Safety; Sampling; Secondary Neoplasm; Secondary Tumor; Serum, Plasma; Severe Combined Immunodeficient Mice; Site; Small Business Innovation Research; Small Business Innovation Research Grant; Solid Neoplasm; Solid Tumor; Staging; TAM; Tamoxifen; Testing; Time; Tissue Expansion; Tissue Sample; Tissues; Toxic effect; Toxicities; Transplantation, Heterologous; Treatment Compliance; Treatment Efficacy; Tumor Cell Migration; Tumor Tissue; Tumor-Specific Treatment Agents; White Blood Cells; White Cell; Xenograft; Xenograft Model; Xenograft procedure; Xenotransplantation; [(1R,-2R)-1,2-cyclohexanediamine-N,N'][oxalato (2--)-O,O']platinum; anticancer agent; anticancer drug; biomarker; cancer metastasis; cancer type; canine; clinical investigation; colon cancer cell line; compliance cooperation; dFdC; dFdCyd; data modeling; design; designing; disease/disorder; domestic dog; drug efficacy; drug/agent; experiment; experimental research; experimental study; gemcitabine; gene product; in vivo; inhibitor; inhibitor/antagonist; kinase inhibitor; liquid chromatography mass spectrometry; malignancy; model organism; mouse model; neoplasm/cancer; novel; oncology; oxalato (1R,2R-cyclohexanediamine)platinum(II); oxalato (trans-l-1,2-diaminocyclohexane)platinum(II); oxalato-(1,2-cyclohexanediamine)platinum II; oxaliplatin; oxaliplatine; patient adherence; patient population; phase 1 study; phase 1 trial; phase 2 study; phase 2 trial; phase 3 study; phase 3 trial; phase I trial; phase II trial; phase III trial; platinum(II)-1,2-cyclohexanediamine oxalate; preclinical evaluation; protocol, phase I; protocol, phase II; protocol, phase III; public health relevance; research study; response; severe combined immune deficiency; src Kinases; src Tyrosine Kinases; src-Family Kinases; src-Family Tyrosine Kinases; study, phase II; study, phase III; success; therapeutic efficacy; therapeutically effective; therapy compliance; therapy cooperation; tool; trans-l DACH oxalatoplatinum; trans-l diaminocyclohexane oxalatoplatinum; tumor; tumor growth; white blood cell; white blood corpuscle