?Cancer is a major public health problem and a leading cause of mortality, claiming more than half million lives every year in the US. While major progresses have been made in developing targeted anticancer therapeutics, many cancers such as lung cancers have no effective treatments. Unfortunately, many ideal oncogenic targets including transcription factors for these cancers are considered "undruggable" and simply avoided for discovery of targeted therapeutics. STAT3, a transcription factor in the Janus kinase (JAK)/STAT signaling pathway, is constitutively activated in most human cancers including lung and breast cancers and has been shown to drive tumorigenesis. Thus, STAT3 is a sought-after target for discovery of anticancer drugs. Indeed, targeting the SH2 domain of STAT3 for drug discovery has been attempted. However, the clinical efficacy of these inhibitors is limited and some are poorly tolerated in humans. On the other hand, targeting the DBS of STAT3 has not been in the main stream of research due to the taboo that the DNA-binding site (DBS) is "undruggable". Using an improved in-silico screening approach, a STAT3-selective small molecule inhibitor (inS3-54) targeting the DBS of STAT3 was recently identified, which effectively inhibits cancer cell proliferation, migration, and invasion. These findings suggest tha the DBS of STAT3 may be druggable, challenging the prevailing dogma of DBS as an "undruggable" site and may promise a potential therapeutics for the difficult to treat human cancers. The long-term objective of QRKanswer, LLC, an Indiana-based small business, is to investigate inhibitors targeting the DBS of STAT3 for potential drug development. In this Phase I STTR application, QRKanswer and its research partners at Indiana University School of Medicine plan to investigate the active analogues of inS3-54 and newly synthesized new composition of matters to identify lead inhibitors for potential anticancer drug development. To this end, two aims will be accomplished to (1) evaluate the active inS3- 54 analogues and new composition of matters using in-vitro cell-based assays and (2) evaluate the lead analogues for preclinical pharmacokinetics, toxicity, and efficacy. At the conclusion of this study, QRKanswer will have a lead inhibitor targeting the DBS of STAT3 with preclinical data for Phase II study, in which QRKanswer will further investigate the lead compound for filing IND and potentially testing safety in phase I clinical trial of solid tumors such as breast and lung cancers with estimated 234,190 and 221,200 new cases in 2015, respectively. The successful outcome will help QRKanswer gain entry into this market.
Public Health Relevance Statement: Public Health Relevance: Human cancer is a major public health issue, claiming more than half million lives in the US alone. In this Phase I STTR application, QRKanswer, an Indiana-based small business and its research partners at Indiana University School of Medicine, plans to develop novel inhibitors targeting STAT3 molecule, which is constitutively activated in human cancers, by challenging the prevailing dogma of "undruggable" DNA-binding sites of transcription factors. The outcome is expected to have significant impact on treatment of human cancers and on drug discovery targeting the "undruggable" oncogenic targets.
Project Terms: Active Sites; analog; Animal Model; anti-cancer therapeutic; Antineoplastic Agents; Apoptosis; base; Binding; Binding Sites; Biological Assay; Breast Cancer Model; Businesses; cancer cell; Cancer cell line; cancer therapy; Categories; Cell Line; Cell Proliferation; Cells; clinical efficacy; Computer Simulation; Data; Development; Disease; DNA Binding; DNA-Binding Proteins; drug development; drug discovery; Drug Kinetics; effective therapy; EMSA; Evaluation; falls; Human; improved; In Vitro; in vivo; Indiana; inhibitor/antagonist; Janus kinase; Lead; Lung; malignant breast neoplasm; Malignant neoplasm of lung; Malignant Neoplasms; Marketing; Maximum Tolerated Dose; medical schools; member; migration; mortality; new therapeutic target; novel; Oncogenic; Outcome; overexpression; Phase; phase 1 study; phase 2 study; Phase I Clinical Trials; Play; pre-clinical; Proteins; Public Health; public health relevance; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; safety testing; screening; Signal Pathway; Site; Small Business Technology Transfer Research; small molecule; small molecule inhibitor; Solid Neoplasm; src Homology Region 2 Domain; STAT1 gene; Stat3 protein; Stat5 protein; Stream; Taboo; targeted treatment; Therapeutic; Time; Toxic effect; transcription factor; triple-negative invasive breast carcinoma; tumorigenesis; Universities; Western Blotting; Xenograft procedure
