COT.V: Critical Outcome Technologies: A Unique, Proprietary Technology, CHEMSASĀ®, for Drug Discovery and Development
OVERVIEW Critical Outcome Technologies Inc. (COT.V) is a clinical stage biopharmaceutical Company which is focused on the discovery and development of cancer treatments through targeted therapeutics. The Company has developed a proprietary artificial intelligence platform, CHEMSASĀ®, which utilizes a series of predictive computer models to identify compounds with a high probability of being successfully developed from disease specific drug discovery through chemical optimization and preclinical testing. The CHEMSASĀ® platform technology is focused on small molecules, and as a drug candidate discovery engine can be applied to any disease target with a modest amount of information for the target of interest. The CHEMSASĀ® technology uses machine learning to rapidly develop targeted therapies thereby dramatically reducing the timeline and cost of getting new drug therapies to market. Based on the CHEMSASĀ® technology, COTI has built a robust pipeline with focus on cancer therapy. The Company's lead compound, COTI-2, has a novel p53-dependent mechanism of action with selective and potent anti-cancer activity. COTI-2 entered into a human clinical Phase I trial near the end of 2015. COTI is developing COTI-2 for gynecologic cancers, including ovarian, cervical, and endometrial. The Company is also developing drug candidates for the treatment of acute myelogenous leukemia, colorectal cancer, small cell lung cancer, MRSA, multiple sclerosis, Alzheimerās disease, and HIV. Critical Outcome Technologies Inc. was originally founded as a private company in 1999 and is based in London, Canada. The Company went to public in 2006 and its shares are listed on the TSX Venture Exchange under the trading symbol of COT.V and in the United States on the OTCQB under the trading symbol of COTQF. The Unique CHEMSASĀ® Drug Discovery and Development Technology Over the years, COTI has developed a unique, proprietary platform technology, CHEMSASĀ® (Computerized Hybrid Expert Molecular Structure Activity Screening), a machine learning (artificial intelligence, AI) based drug discovery and development platform technology. CHEMSASĀ® Ā® is a multi-staged computational platform technology based upon a hybrid of machine learning technologies and proprietary algorithms that allow accurate predictions of biological activity from the molecular structure. In order to accurately predict the biological activity of a molecule, the series of proprietary algorithms are applied to complex 3D molecular structures of the molecule to produce unique 2D data patterns composed of more than 250 descriptors. These unique 2D molecular data patterns are then used to develop hybrid predictive models relating molecular structure to specific target biological properties that traditionally require expensive and time consuming in vitro or in vivo tests. The final lead candidates are selected based on an optimal profile of probable physical chemical, biological, efficacy and ADMET properties. To ensure that CHEMSASĀ® remains a cutting edge technology, new and updated prediction models are being constantly added and refined. New molecules are continuously being added to the database and new in silico versions of tests and assays are also being developed in order to make CHEMSASĀ® predictive capability as comprehensive as possible. CHEMSASĀ® has competitive advantages over traditional drug discovery methods. COTIās discovery/optimization takes only about 3 months to establish a final library of 6-10 promising candidates. A summary of the process is set out in the graphic below. Using this methodology, COTI can establish a 1 st generation compound library of 1000-1500 structures in about 2-3 months. Then, a 2 nd generation library undergoes final computational profiling leading to a final library of 6-10 potential leads. After the final leads are selected, COTI will conduct a patent search on the most promising candidates to establish composition of matter patentability. After the lead candidates are selected, the Company will license or develop the most promising ones into preclinical and clinical studies. The end results are a shortened period of time and higher probability of success for the drug discovery and development phase which can save millions of dollars and increase the revenue period under patent protection and minimize regulatory risk. Further, this platform is designed to repeatedly identify high probability compounds and quickly build a pipeline targeting multiple unmet medical needs. COT-2: A Novel Activator of p53 Targeting Multiple Cancers COTI-2 is a novel small molecule discovered using the Companyās CHEMSASĀ®Ć discovery engine. COTI-2 is a 3 rd generation thiosemicarbazone engineered for low toxicity and designed as an oral treatment of susceptible cancers. COTI-2 restores p53 function to a wide range of common p53 mutations and also acts as a negative modulator of the PI3K/AKT/mTOR pathway. Background of the p53 Pathway p53 is a multifunctional tumor suppressor protein that regulates many important cellular responses, such as cell growth arrest and apoptosis, to environmental/external stress. p53 is encoded by the TP53 gene in humans and has been widely regarded as possibly holding a key to the future of cancer therapies. In response to cellular stress, wild-type p53 induces cell cycle arrest and/or apoptotic cell death. p53 is regulated primarily by ubiquitin ligase MDM2, which binds to p53 and activates downstream anti-cancer gene expression which kills cancer cells by promoting cell cycle arrest, apoptosis and senescence. Mutant p53 protein is the single most important cancer causing gene mutation known, is often found at high levels in more than 50% of human cancers and contributes to the transformation of cancer cells, metastasis and drug resistance. Mutations not only disable the p53 tumor suppressive function but also exhibit cancer-promoting activity by gaining oncogenic properties. Mutant p53 is an array of mutant proteins with oncogenic properties that varies among patients. Reactivation of wild type p53 to restart apoptosis is an effective way to kill cancer cells. COTI-2 is a Potent Activator of Mutant p53 Data indicates that COTI-2 normalizes mutant p53 to wild-type-like conformation to promote apoptosis/cell death. The mechanism is most likely through zinc chelation by COTI-2ās thiosemicarbazone core structure. Metal ion chelation has been shown to induce p53 conformational changes. Wild-type p53 binds zinc and requires it for proper function. Mutant p53 is relatively unable to bind zinc. Metal chelation by a thiosemicarbazone is hypothesized to provide a source of zinc that allows for a p53 mutant conformation change. Thiosemicarbazones induce a wild-type-like conformational change in the p53 mutant protein that restores sequence-specific p53 transcription. Research has shown that COTI-2 activity is strongly correlated with p53 status. A bioinformatics analysis of the NCI molecular targets database demonstrated that low COTI-2 IC 50 was strongly associated with the presence of any p53 mutation, and that low COTI-2 IC 50 was also strongly associated with the presence of p53 hotspot mutations occurring at amino acids 175, 248, and 273 . Extensive preclinical studies demonstrated COTI-2ās ability to restore mutant p53 function and thus induce cancer cell death in many common p53 mutations. COTI-2 has demonstrated nanomolar activity in vitro and in vivo as a single agent against multiple cancer cell lines from various cancer types including small cell lung, non-small cell lung, colon, brain, ovarian, endometrial, triple negative breast, head and neck, and pancreatic. COTI-2 is more efficacious relative to standard chemotherapeutic agents in many cell types. In preclinical cell line studies, COTI-2 exhibited more potent activity against human brain cancer cell lines than temozolomide, cisplatin (Platinol Ć ), and BCNU. COTI-2 was also more potent than Gleevec Ć (Imatinib mesylate) in lung cancer cells. In combination studies, COTI-2 enhanced the activity of standard chemotherapeutic agents including Taxol, Cisplatin, Tarceva, and Erbitux. In DMS114 SCLC cells, COTI-2 in combination with either Taxol or Cisplatin (CDDP Ć ) had a greater-than-additive effect (indicated by differences between data points at each concentration) where indicated by asterisks. Similar results were obtained with Carboplatin. In human colon cell lines, COTI-2 enhanced the effectiveness of Erbitux Ć regardless of KRAS status. Studies also showed that, COTI-2 induced no significant resistance or cross-resistance in SCLC cell lines (DMS-114 and SHP-77). Drug resistance remains one of the most pressing problems in the management of cancer patients. In this regard, COTI-2 may provide physicians an alternative to many existing cancer treatment regimes. COTI-2 significantly reduced p53 mutant protein levels and significantly increased wild-type p53 protein levels in TOV-112D ovarian cells likely by inducing a conformational change. While COTI-2 had no significant effect on p53 protein levels in the H460 non-small cell lung cancer cell line, which does not carry the mutant p53 protein. In a preclinical study using OVCAR-3 ovarian cancer cell line, COTI-2 significantly reduced tumor volume in a dose dependent manner. Multiple in vivo xenograft models indicate that COTI-2 does not exhibit any overt signs of toxicity. Available PK data suggests that COTI-2 can be administered orally once daily or less. Blood levels of COTI-2 following single oral dose maintained >> IC 50 for more than 48 hours. READ THE FULL INITIATION REPORT HERE SUBSCRIBE TO ZACKS SMALL CAP RESEARCH to r ec eive o ur articles and reports emailed directly to you each morning. Please visit our website for additional information on Zacks SCR and to view our disclaimer.
CHEMSASĀ® drug discovery process only takes about 15 months from discovery/optimization, while traditional drug discovery processes can take 36-42 months.
First, CHEMSASĀ® can accelerate identification of drug candidates. This faster time to market saves millions of dollars for drug discovery and development and yields increased profits for each successful new drug by providing a longer revenue period under the patent life.
In addition to time savings, this rigorous scientific screening process allows customers to fill their pipelines with drug candidates that have a higher probability of clinical success.
