SBIR-STTR Award

There is an unmet need to inhibit the key cancer promoting transcription factor MYC. MYC (both cMYC and MYCN) acts downstream of many cell receptor complexes and signal transduction pathways to activate genes that drive cancer cell growth and proliferation. To date, small molecule inhibitors of MYC have been elusive. An innovative approach would be to indirectly orthogonally diminish the activity of MYC by enhancing its degradation using PI-3 kinase (PI-3K) inhibitors combined with blocking transcription of the gene producing MYC using inhibitors of the bromodomain protein BRD4. While small molecule inhibitors or PI-3K and BRD4 are individually used in cancer clinical trials, none has made it through development to FDA approval. Although combination treatments are common in cancer, there is an unmet need for every increasing combinations to inhibit multiple targets to maximize efficacy. This becomes unfeasible due to prohibitive costs when combining expensive targeted therapies in addition to being a barrier to early clinical evaluation of such complex combinations of drugs. While exploring a novel PI-3K inhibitor scaffold, thienopyranone (TP) scaffold based on a chromone derivative we discovered that these compounds also can potently inhibit BRD4 (preliminary results). The chromone backbone is common to the inhibition of BOTH targets thus providing the opportunity to now explore the newly found BRD4 activity while maintaining potent PI-3K activity (overall objective). Consolidating the inhibition of PI-3K AND BRD4 to maximally inhibit MYC activity with one molecule would fill all the unmet needs stated above. This proposal will evaluate this approach by achieving the following aims setting the stage for phase II efforts to optimize the expected dual inhibitor lead compound(s) to a clinical candidate: Aim (Task) #1. Determine structure activity relationship (SAR) for TP compounds for BRD4 inhibition. Approach: Synthesize 30 TP compounds and determine their BRD4 and PI-3K inhibition profiles. Aim (Task) #2. Develop predictive computational BRD4 model for the in silico docking of designed compounds. Approach: Vary the molecular in silico fit parameters of the BRD4 model until docking predictions of a TP dataset correlates with actual BRD4 assay binding results creating a validated docking model. Aim (Task) #3. Determine effects on MYC and therapeutic index for dual BRD4/PI-3K inhibition. Approach: Determine MYC expression and activity levels and compare toxicity towards cancer cell lines versus normal cell lines when exposed to single BRD4 or PI-3K versus dual BRD4/PI-3K inhibition conditions. The contribution of this research is it provides an effective mechanism to block MYC activity that drives cancer and will be significant because it will allow enhanced combination treatments of MYC dependent cancers, such as CLL, medulloblastoma, and neuroblastoma. This approach is innovative because it attacks a key cancer target using two orthogonal mechanisms with a single compound and it challenges the cost-ignoring efficacy-limiting mentality of one-drug one-target prevalent in cancer research in an area with no FDA approved treatments.

Public Health Relevance Statement:


Public Health Relevance:
The planned research is relevant to public health because data we and others have acquired shows that our proposed development of a potent new PI3 kinase-BET dual inhibitor to target cancer cells dependent upon the Myc oncogene. Moreover, the proposal is designed to produce a platform technology for the development of dual small molecule inhibitors of PI3K combined with inhibitors of other targets, thereby having a broad impact on public health. Thus the proposed research which will involve a close collaboration between academia and industry is relevant to the part of the NIH's mission that pertains to the development of new therapeutics able to reduce the burden of human disability via improved treatment of adult and childhood cancer.

Project Terms:
1-Phosphatidylinositol 3-Kinase; Academia; Adult; angiogenesis; anticancer activity; anticancer research; Area; Back; base; Binding (Molecular Function); Binding Sites; Biological Assay; Bromodomain; c-myc Genes; cancer cell; Cancer Cell Growth; Cancer cell line; Cancer Patient; Cancer stem cell; cancer therapy; Catalytic Domain; Cell Line; Cell Proliferation; Childhood; Childhood Solid Neoplasm; Chromatin; Chromones; Clinic; Clinical; Clinical Trials; Collaborations; common treatment; Complex; Computer Simulation; cost; Data; Data Set; design; Development; disability; Docking; Drug Combinations; Epigenetic Process; Evaluation; FDA approved; Genes; Genetic Transcription; Goals; Growth; Human; improved; In Vitro; Individual; Industry; inhibitor/antagonist; Inhibitory Concentration 50; innovation; kinase inhibitor; Knowledge; knowledge base; Laboratories; Lead; Literature; Lysine; Malignant Childhood Neoplasm; Malignant Neoplasms; medulloblastoma; Mission; Mitotic Cell Cycle; Modeling; Molecular; molecular modeling; Molecular Models; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Mus; MYC gene; MYCN gene; Neoplasm Metastasis; Neuroblastoma; Neurons; Nodal; Normal Cell; novel; novel therapeutics; Outcome; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Process; Property; Proteins; Proto-Oncogene Proteins c-myc; Proto-Oncogenes; public health medicine (field); public health relevance; Receptor Cell; Reporting; Research; research clinical testing; Resistance; scaffold; Signal Transduction; Signal Transduction Pathway; single molecule; small molecule; Staging; Stem cells; Structure-Activity Relationship; technology development; Therapeutic; Therapeutic Agents; Therapeutic Index; Toxic effect; transcription factor; tumor; tumor progression; Vertebral column; Work

There is an unmet need to inhibit the key cancer promoting transcription factor MYC (both c-MYC and MYCN) that act downstream of many cell receptors and signal transcription pathways to activate genes for cancer cell resistance and tumor growth. To date, small molecule inhibitors of MYC have remained elusive. In our Phase I STTR (CA192656), we developed a lead compound, SF2523 which displays potent orthogonal inhibitory activity against MYC by blocking PI-3 kinase (PI-3K) and the highly dominant regulator of epigenetic machinery, BRD4. The objective of this application will be to develop SF2523 through advanced preclinical studies for therapeutic application in this Phase II STTR proposal. The transcription factor, MYC (c-MYC and MYCN) plays a key role in cancer growth, proliferation, survival, and it is overexpressed in a subgroup of most human cancers resulting in resistance to PI-3K and other signaling pathway inhibitors. Both MYC and PI-3K are well-established onco-proteins that are confirmed drivers in a large number of tumor types. Moreover, BRD4 is rapidly emerging as a dominant epigenetic regulator of the transcriptome and of cancer cell resistance to kinase inhibition. Therefore, there is general consensus in the cancer biology arena that inhibition of BRD4 and/or MYC should prove beneficial in multiple cancers where MYC is an established regulator of tumor cell transformation and resistance. Our innovative approach centers on our central hypothesis that a dual PI-3K/BRD4 inhibitor, SF2523, will potently inhibit MYC activity by enhancing its degradation via PI-3K inhibition AND blocking MYC transcriptional activity via BRD4 inhibition. Our Phase I STTR Specific Aims successfully solved the crystal structure of SF2523 in the active site of BRD4 and determine the structure activity relationships around dual PI-3K/BRD4 inhibitors designed by validated molecular modeling studies and demonstrated the safety of our dual-targeting single inhibitor versus the accumulated toxicity of using two separate inhibitors. Our successful Phase I studies set the stage for our selection of SF2523 as the candidate for preclinical development to treat PI-3K/MYC dependent malignancies in Phase I trials as a clinical development strategy. The significance of this Phase II proposal is that it will advance SF2523 through preclinical development and validate this novel dual PI-3K/BRD4 inhibitor as a drug candidate against PI-3K/MYC-driven malignancies with high mortality rates e.g. hepatocellular carcinoma (HCC) and squamous cell carcinoma of the head/neck (SCCHN) and obtain a back-up candidate by further evaluation of SF2523 analogs found from Phase I SAR studies. Moreover, our aims in Phase II will identify PI-3K and MYC tumor signatures and a companion diagnostic approach which will define sensitivity to SF2523 as we move toward FDA registration and commercialization of this “first in class” dual PI-3K/BRD4 inhibitor chemotype in cancer therapeutics.

Public Health Relevance Statement:
Project Narrative The planned research is relevant to public health because data we and others have acquired shows that our proposed Phase II development of a potent novel PI3 kinase-BRD4 dual inhibitor to target MYC oncogenesis in cancer cells. Moreover, the proposal is designed to produce a platform technology for the development of dual small molecule inhibitors of PI3K combined with inhibitors of other targets, thereby having a broad impact on public health. Thus the proposed research which will involve a close collaboration between academia and industry is relevant to the part of the NIH’s mission that pertains to the development of new therapeutics able to reduce the burden of human disability via improved treatment of adult and childhood cancer.

Project Terms:
1-Phosphatidylinositol 3-Kinase; Academia; Active Sites; Adult; Alcohols; analog; Animals; Automobile Driving; Award; Back; base; BAY 54-9085; Binding Sites; Blood; c-myc Genes; Cancer Biology; cancer cell; Catalytic Domain; cell transformation; Cells; Childhood; Childhood Solid Neoplasm; Clinical; clinical candidate; clinical development; Clinical Trials; Collaborations; Combined Modality Therapy; commercialization; companion diagnostics; Computer Simulation; Consensus; Crystallization; Data; design; Development; disability; Dose; drug candidate; efficacy study; Epigenetic Process; Evaluation; Excipients; Exposure to; Formulation; Genetic Transcription; Goals; Growth; Head and Neck Squamous Cell Carcinoma; Human; improved; Industry; inhibitor/antagonist; innovation; insight; kinase inhibitor; knock-down; Lead; Lysine; Malignant Childhood Neoplasm; Malignant Epithelial Cell; Malignant Neoplasms; MAP Kinase Gene; Maximum Tolerated Dose; medulloblastoma; Mission; Modeling; molecular modeling; Molecular Models; Morbidity - disease rate; mortality; Mus; Mutation; MYCN gene; neoplastic cell; Neuroblastoma; Normal Cell; novel; novel therapeutics; Oncogenes; Oncoproteins; Oral; overexpression; Particle Size; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; phase 1 study; phase I trial; Phosphotransferases; PIK3CA gene; Play; pre-clinical; preclinical development; preclinical study; Primary carcinoma of the liver cells; prognostic significance; Public Health; Ras/Raf; Rattus; Receptor Cell; Receptor Signaling; Research; Resistance; response; Route; Safety; safety study; scale up; Schedule; Signal Pathway; single molecule; Small Business Technology Transfer Research; small molecule; small molecule inhibitor; Structure; Structure-Activity Relationship; Study models; Subgroup; Technology; technology development; Therapeutic; Therapeutic Studies; therapeutic target; Toxic effect; transcription factor; transcriptome; tumor; tumor growth; tumorigenesis; United States National Institutes of Health; Viral