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Company
Portfolio Data
Back to Company SearchCarmot
Address
409 Illinois StreetSan Francisco, CA, -
USA
UEI: N/A
Number of Employees: 5
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
SBIR/STTR Involvement
Year of first award: 2010
4
Phase I Awards
2
Phase II Awards
50%
Conversion Rate
$1,340,639
Phase I Dollars
$2,411,764
Phase II Dollars
$3,752,403
Total Awarded
Awards
Drug candidates that disrupt the NEMO/IKK signaling complex for the treatment of
Amount: $1,911,764 Topic: NCI
DESCRIPTION: Drug candidates that disrupt the NEMO/IKK signaling complex for the treatment of cancer Project Summary/Abstract Protein-protein interactions represent the largest untapped opportunity for therapeutic development, but the field has languisheddue to lack of efficient lead finding technologies. To address these shortcomings, Carmot is developing an innovative drug discovery technology called Chemotype Evolution. Chemotype Evolution provides access to novel and target-relevant chemical diversity with an efficiency that is unprecedented with other technologies. Importantly, through iterative applications of Chemotype Evolution, a starting peptide can be evolved into smaller and more drug-like molecules. Carmot has successfully applied this approach to target the NEMO/IKK protein-protein interaction, a key mediator of NF-kB activation. This Phase II proposal will advance the promising hits identified during Phase I to support Carmot's long-term objective to develop drugs that inhibit cancer cell survival and inflammatory signaling in the tumor environment by inhibiting NF-kB activation. The NF-kB pathway is critical for the progression of leukemia and lymphoma and is directly activated by several cancer-associated mutations. NF-kB is also a key signaling node in the communication between tumors and the inflammatory microenvironment by promoting inflammation, cell survival, cell proliferation, angiogenesis, and tissue remodeling. However, despite intensive efforts, viable drug-leads that specificallytarget NF-kB activation have not been identified. The protein-protein interaction between NF-kB Essential Modulator (NEMO) and IkB Kinase (IKK), referred to as NEMO/IKK, has emerged as a promising target for inhibiting NF-kB activation. The technical objective of this Phase II proposal is to advance NEMO/IKK inhibitors identified in Phase I toward proof-of-concept in animal models. Specifically, Carmot will use Chemotype Evolution and medicinal chemistry to improve potency, cell activity, and pharmaceutical properties (aim 1). Next, Carmot will test compounds as single agents and in combination with approved chemotherapeutics in cell-based models of lymphoma and evaluate markers of drug response (aim 2). Finally, select compounds will be tested in animal models of lymphoma with the goal of identifying drug candidates for further pre-clinical development (aim 3). Two products will emerge from the Phase II research. First, this proposal will validate an innovative technology for targeting protein-protein interactions by progressively converting a peptide ligand into a smaller more drug-like molecule, thus addressing a major technological gap in pharmaceutical discovery. Second, the identified molecules will serve as new drug candidates for treatment of leukemias, lymphomas, and solid tumors. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Drug candidates that disrupt the NEMO/IKK signaling complex for the treatment of cancer Relevance Inflammatory signals play an essential role in the progression of human cancer and present a promising avenue for therapeutic intervention. The proposed research employs an innovative strategy for targeting inflammatory signaling in tumor tissue. The objective is to identify drug candidates for treating lymphoma, leukemia, and solid tumors.
Tagged as:
SBIR
Phase II
2013
HHS
NIH
Discovery of biased small molecule agonists of the GLP-1 receptor for treatment o
Amount: $541,527 Topic: NIDDK
DESCRIPTION (provided by applicant): Type 2 diabetes mellitus is one of the most challenging health problems of the 21st century. Global health care expenditures to treat diabetes and its complications are estimated to have been 376 billion in 2010, of which 198 billion was spent in the United States. Efficacious and convenient pharmaceutical interventions are urgently needed to slow this global pandemic. Glucagon-like peptide 1 (GLP-1) and its receptor have emerged as one of the most promising avenues for intervention. GLP-1 is a 30 amino acid peptide hormone that binds to the GLP-1 receptor (GLP-1R), a G-protein coupled receptor (GPCR) that stimulates insulin secretion and controls blood glucose. Modified GLP-1 and GLP-1 analogs are approved for the treatment of type 2 diabetes in all major markets. However, these drugs must be injected daily, limiting their acceptance by patients. An orally available small molecule GLP-1 receptor agonist would be a significant advance in diabetes treatment. The long-term objective of this proposal is to develop orally available drugs that activate GLP-1R. Carmot has identified multiple GLP-1R agonists with potential for oral bioavailability. As Carmot advances these agonists toward the clinic, implementation of biological assays to identify the best drug candidates will be crucial, especially in light of growing evidence that GPCRs may engage subsets of available signaling pathways, a concept known as biased agonism. Indeed, the GLP-1R has been shown to signal through both G-protein and b-arrestin mediated pathways. However, the relative importance of these distinct pathways in promoting insulin secretion is not understood, primarily due to a lack of pharmacological agents that differentiate between these two pathways. Carmot is in the unique position to address this question, having identified chemically diverse agonists that, in preliminary studies, show varying degrees of biased agonism. The goal of this Phase I proposal is to clarify the role of biased agonism in GLP-1R signaling and insulin secretion, and then to use these insights to not only identify compounds that closely mimic the agonism bias of GLP-1 but also to discover molecules with different profiles. Compounds with distinct profiles will be tested in rodentdiabetes models as part of a Phase II proposal to characterize their pharmacological properties. Importantly, compounds with different profiles than GLP-1 could have superior efficacy for treating diabetes and other metabolic disorders. The specific aimsof this Phase I proposal are 1) to analyze Carmot's more than 24,000 GLP-1R directed molecules for biased agonism, especially current lead molecules; 2) to determine the importance of biased agonism in stimulating insulin secretion from pancreatic islets;3) to determine internalization kinetics and endocytic trafficking of select compounds, including GLP-1. To ensure the success of this endeavor, Carmot is proposing to bring in an experienced PI, who currently works in academia and has more than a decade of experience working with GPCR signals and endocytic sorting in cell based and animal models. PUBLIC HEALTH RELEVANCE: Worldwide there are more than 250 million people with type 2 diabetes. Safe, efficacious, and simple to use therapies are urgently needed to increase patient compliance and reduce the associated health care burden. This proposal is based on a clinically proven approach and aims to discover an oral pill for treatment of diabetes that will eliminate the need for patients to take daily injections.
Tagged as:
SBIR
Phase I
2012
HHS
NIH
A novel approach to discover selective small molecule inhibitors of FABP4 and FAB
Amount: $299,807 Topic: NIDDK
DESCRIPTION (provided by applicant): A novel approach to discover selective small molecule inhibitors of FABP4 and FABP5 for the treatment of metabolic diseases The Western diet and lifestyle has brought an epidemic of health problems collectively referredto as metabolic syndrome. Obesity plays a central role, contributing to type 2 diabetes, fatty liver disease, atherosclerosis, and degenerative disorders including dementia, airway diseases, and even some cancers. Diet and exercise are the best means to tackle metabolic diseases but often fail to halt disease progression, and pharmacological intervention is often necessary. Among the many potential drug targets for tackling metabolic disorders, two members of the family of fatty acid-binding proteins (FABPs) are particularly compelling. The FABPs consist of nine distinct but closely related proteins; as their name suggests, they play major roles in transporting fatty acids throughout cells and in maintaining metabolic homeostasis. Experiments in rodents suggest that reducing the activity of either FABP4 or FABP5 has moderate effects on a variety of metabolic indicators, but that reducing the activity of both FABP4 and FABP5 provides significant benefits protecting against obesity, insulin resistance, atherosclerosis, and even extends lifespan. However, effective and safe drugs must be highly selective: reducing the activity of FABP2 causes weight gain and elevated insulin levels, while reducing the activity of FABP3 causes heart problems. This Phase I SBIRhas three specific aims. In the first aim, Carmot will apply a novel small molecule lead discovery technology called Chemotype Evolution to FABP4 with the goal of discovering at least 20 potent inhibitors. Chemotype Evolution is a fragment-based approach designed to find selective inhibitors against difficult protein targets, and so fulfilling the first goal will not only identify useful molecules but also demonstrate that the technology can deliver a wide variety of starting points for a therapeutically important target. In the second aim, Carmot will explore selectivity against FABP2, FABP3, and FABP5. The goal is to discover at least 5 compounds with high potency against both FABP4 and FAPB5 and good selectivity against FABP2 and FABP3. This will demonstrate that the technology can deliver selective inhibitors against closely related members of a single protein family. The third aim is to identify at least two compounds with the desired selectivity profile that also show good cell-based potency. These molecules will certainly be useful tools for dissecting the FABP pathways. More importantly, these molecules could be potential therapeutics for treating a variety of metabolic diseases, including obesity and diabetes. The goal of a Phase II SBIR would be to further develop the resulting molecules in preclinical animal models prior to human development. PUBLIC HEALTH RELEVANCE: A novel approach to discover selective small molecule inhibitors of FABP4 and FABP5 for the treatment of metabolic diseases This proposal is to use a powerful new drug discovery technology to identify highly selective inhibitors of two proteins implicated in a variety of metabolic diseases. These inhibitors will become the starting points for new therapeutics to treat unmet medical needs such as obesity and diabetes.
Tagged as:
SBIR
Phase I
2011
HHS
NIH
SBIR Phase II: A new drug discovery method to transform peptides to small molecules: proof of principle with p53-hdm2
Amount: $500,000 Topic: Phase II
This Small Business Innovation Research (SBIR) Phase II project creates a powerful drug discovery technology that uses an innovative fragment-based approach to identify small molecule inhibitors of difficult targets. Though many peptides can disrupt protein-protein interactions, conventional screening technologies are rarely successful at identifying small molecules that do so. In this project peptides are transformed into smallmolecule drugs through an iterative, systematic, empirical screening approach, whereby a small molecule can be evolved to harness key binding properties of peptide-based inhibitors. This proprietary technology, Chemotype Evolution, will be applied to the anticancer target p53-HDM2. The Phase I/IB grant demonstrated that peptides can be deconstructed into baits suitable for performing Chemotype Evolution. In Phase II, Chemotype Evolution will be used to convert these peptide-based baits into novel, potent, completely non-peptidic inhibitors of the p53-HDM2 interaction. Moreover, the flexibility of the technology will be increased by adding additional chemistries. The broader impacts of this research are two-fold. First, the inhibitors discovered could lead to new drugs for treating cancer. Second, their identification will validate a drug discovery technology that can be applied generally to difficult targets. Routine transformation of peptides into small-molecule drugs would create a wealth of profitable opportunities. Scientifically, this technology will advance the field of molecular recognition and provide a rapid and cost effective method for creating chemical probes to investigate biological pathways. The societal impact will be substantial, as the technology will facilitate the discovery of drugs for unmet medical needs, particularly where conventional technologies have failed.
Tagged as:
SBIR
Phase II
2011
NSF
A new drug discovery method to transform peptides to small molecules: proof of principle with p53-hdm2
Amount: $199,998 Topic: BC
This Small Business Innovation Research (SBIR) Phase I project will advance an innovative drug discovery technology to tackle important disease targets such as protein-protein interactions. Conventional drug discovery technologies are rarely successful at identifying drugs that can disrupt protein-protein interactions. While peptides can disrupt protein-protein interactions, peptides seldom make good drugs. This proposal describes a powerful approach to transform peptides into drug-like molecules. The well-characterized and important anti-cancer target p53-hdm2 will be used as a model system. Peptide inhibitors of the p53-hdm2 interaction have been described in the literature. The objective of this Phase I proposal is to convert these peptides into drug-like molecules. Subsequently, these molecules can be further advanced into drug candidates for treating human cancers. In addition, successful completion of the proposed research will validate a transformative new drug discovery technology. The broader impacts of this research are to develop the technologies to tackle important human disease targets that are not amenable to current drug-discovery approaches. Protein-protein interactions present one of the largest untapped opportunities to develop new therapies. The technology provides a general and systematic method to tackle this target class by efficiently transforming peptides into small molecules. It has the potential to revolutionize the drug discovery process, and thus the commercial opportunity is enormous. In addition, the proposed technology will advance our understanding of drug discovery. The societal impact will be substantial, as the technology will facilitate the discovery of drugs for unmet medical needs.
Tagged as:
SBIR
Phase I
2010
NSF
Discovery of small molecule drug candidates that disrupt the NEMO/IKK signaling c
Amount: $299,307 Topic: NCI
DESCRIPTION (provided by applicant): Protein-protein interactions represent the largest untapped opportunity for therapeutic development. The number of protein-protein interactions in human cells has been estimated to exceed 100,000, well above the ~30,000 human genes. This multitude of protein-protein interactions constitutes a tremendous opportunity for therapeutic innovation as the field has languished due to lack of promising technological approaches. To address the shortcomings in existing technologies, Carmot is developing an innovative lead finding technology called Chemotype Evolution. Chemotype Evolution is a proprietary technology based on the well- validated approach of making and screening target-directed compound libraries, but uses fragment-based concepts to take this approach to a new level. Chemotype Evolution enables an evolutionary screening paradigm that is unprecedented in small molecule drug discovery and provides rapid and inexpensive access to novel and target-relevant chemical diversity that is not easily accessed by other technologies. The long-term objective of this proposal is to develop small molecule drugs that stimulate tumor cell apoptosis and inhibit inflammatory signaling in the tumor environment. The NF-kB pathway is a key signaling node in the communication between tumors and the inflammatory microenvironment. The activities of anticancer drugs bortezomib and thalidomide have in part been attributed to indirect inhibition of NF-kB. Despite intensive efforts, viable drug-leads that directly target NF-kB activation have not been identified. The protein-protein interaction between IkB Kinase (IKK) and Nf-kB Essential Modulator (NEMO), referred to as NEMO/IKK, has emerged as a promising target for inhibiting NF-kB activation: Peptides that encompass the NEMO binding domain (NBD) of IKK can block IKK binding to NEMO and inhibit NF-kB activation in vivo. The specific objective of this Phase I proposal is to discover drug-like inhibitors of NF-kB activation. To achieve this, Carmot will use Chemotype Evolution to evolve NBD peptides into small molecule inhibitors of NEMO/IKK. In the first aim, Chemotype Evolution will be used to discover hybrid molecules of NBD peptides and drug fragments that bind to NEMO. In the second aim, Chemotype Evolution will be used to evolve these hybrids into drug-like inhibitors of IKK binding to NEMO. In the third aim, the best inhibitors will be characterized in more detail to lay the foundation for a Phase II proposal to advance select inhibitors towards drug candidates for treating human cancers. The proposed research will validate Chemotype Evolution as a transformative technology for targeting protein-protein interactions and has high potential both for scientific innovation and for development or products that have significant economic and societal benefits. PUBLIC HEALTH RELEVANCE: Localized inflammation plays an essential role in the progression of human cancer and is a promising target for therapeutic intervention. This proposal offers an innovative strategy for targeting inflammation in tumor tissue. The objective is to identify lead compounds with the potential to become drug candidates for treating human cancers.
Tagged as:
SBIR
Phase I
2010
HHS
NIH