Myc is a key transcriptional regulator due to its critical role in many fundamental cellular processes, such as cell cycle progression and cell growth. Therefore, dysregulation of Myc expression can lead to disease, including cancer. Myc is overexpressed in many human tumors, and it is estimated that 1 in 7 cancer deaths in the United States are resultant of high levels of this oncoprotein. Myc cannot act alone, however, and its oncogenic activity is dependent on heterodimerization with Max. Together, these basic helix-loop-helix leucine zipper (bHLHLZ) proteins interact via a protein-protein interaction (PPI). Notably, a single amino acid substitution within the Myc-Max interaction domain can prevent dimerization. Thus, minor perturbation in the dimer surface can profoundly affect the ability of Myc and Max to interact. This fact strongly supports the idea that it may be possible to identify small molecule inhibitors of the Myc-Max PPI. Sorrento Therapeutics' academic collaborators at The Scripps Research Institute (TSRI), Drs. Kim D. Janda and Peter K. Vogt, recently discovered a new series of small molecule antagonists of the Myc-Max PPI. The most potent member of this class of compounds was found to specifically act by targeting Myc and the Myc-Max PPI with in vitro Kd in the low nanomolar range resulting in strong and specific inhibition of Myc- induced oncogenic transformation and interference with Myc-dependent transcriptional regulation. In this STTR application, we will propose to perform structure-activity relationship (SAR) studies on the lead compound, in vitro studies of the obtained analogs, pharmacokinetic/-dynamic characterization, and in vivo evaluation in xenograft cancer models. These studies will be conducted together with our academic collaborators Drs. Kim D. Janda and Vogt (TSRI) as well as Dr. Michael Cameron (TSRI - Florida). Specifically, the projects of our STTR Phase I grant application are: 1: Structure-activity relationship (SAR) studies of lead compound KDJ-PYR-9; 2: Biological and biophysical characterization of Myc-Max inhibitors; 3: Initial ADME studies and and in vivo evaluation in a xenograft model. The proposed eventual product, a highly effective inhibitor of the Myc-Max interaction and thus, Myc-driven transcription, could be an effective and safe stand-alone and/or member of a "cocktail" therapeutic option for treatment of a number of cancers, including solid and hematological tumors.
Public Health Relevance Statement: Public Health Relevance: Myc is a key transcriptional regulator due to its critical role in many fundamental cellular processes and dysregulation of Myc activity can lead to cancer. In fact, Myc is overexpressed in many human tumors, and it is estimated that 1 in 7 cancer deaths in the United States are resultant of high levels of this oncoprotein. The proposed eventual commercial product, a highly effective inhibitor of the Myc-Max interaction and thus, Myc- driven transcription, could be an effective and safe stand-alone and/or member of a "cocktail" therapeutic option for treatment of a number of cancers, including solid and hematological tumors. Terms: Affect; inhibitor; inhibitor/antagonist; anticancer drug; anticancer agent; Tumor-Specific Treatment Agents; Neoplastic Disease Chemotherapeutic Agents; Cancer Drug; Antineoplastics; Antineoplastic Drugs; Anti-Cancer Agents; Antineoplastic Agents; neoplasm/cancer; malignancy; Malignant Tumor; Cancers; Malignant Neoplasms; Cellular Growth; Cellular Expansion; cell growth; Subcellular Process; Cellular Process; Cellular Physiology; Cellular Function; Cell Process; Cell Function; Cell physiology; Death; Cessation of life; disease/disorder; Disorder; Disease; Florida; Future; Modern Man; Man (Taxonomy); Human; In Vitro; heavy metal lead; heavy metal Pb; Pb element; Lead; Libraries; Minor; Oncoproteins; Oncogene Products; Oncogene Proteins; Pharmacokinetics; Drug Kinetics; gene product; Proteins; Research Institute; social role; Role; Safety; structure function relationship; chemical structure function; Structure-Activity Relationship; Transcription; RNA Expression; Gene Transcription; Genetic Transcription; United States; Leucine Zippers; MYC-Associated Factor X; Max protein; analytical method; base; method development; Surface; Phase; Biological; Series; Evaluation; analog; Solid Tumor; Solid Neoplasm; helix turn helix; helix loop helix; HTH Motifs; HTH DNA Binding Domain; Helix-Turn-Helix Motifs; Therapeutic; scaffolding; scaffold; Protein Dimerization; Dimerization; Malignant Hematologic Neoplasm; Hematopoietic Cancer; Hematological Tumor; Hematological Neoplasms; Hematological Malignancies; Hematologic Malignancies; Hematologic Cancer; Hematologic Neoplasms; Xenotransplantation; Xenograft; Heterologous Transplantation; Heterograft; Xenograft procedure; Amino Acid Substitution; dimer; member; Modeling; LOINC Axis 2 Property; Property; protein protein interaction; anticancer therapy; Malignant Neoplasm Treatment; Malignant Neoplasm Therapy; Cancer Treatment; cancer therapy; Transcriptional Control; Transcription Regulation; Transcriptional Regulation; preventing; prevent; small molecule; Absorption, Distribution, Metabolism, and Excretion Study; ADME Study; cytotoxic; Data; Grant Proposals; Applications Grants; Heterodimerization; in vivo; CancerModel; Cancer Model; Cell Cycle Progression; STTR; Small Business Technology Transfer Research; Xenograft Model; Process; Therapeutic Effect; developmental; Development; preclinical; pre-clinical; tumor xenograft; Oncogenic; tumor; overexpress; overexpression; public health relevance; drug candidate; biophysical parameters; biophysical measurement; biophysical characterization; biophysical characteristics; biophysical properties
