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Davis B.J.,Vernalis | Erlanson D.A.,Carmot Therapeutics, Inc.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

In the past 15 years, fragment-based lead discovery (FBLD) has been adopted widely throughout academia and industry. The approach entails discovering very small molecular fragments and growing, merging, or linking them to produce drug leads. Because the affinities of the initial fragments are often low, detection methods are pushed to their limits, leading to a variety of artifacts, false positives, and false negatives that too often go unrecognized. This Digest discusses some of these problems and offers suggestions to avoid them. Although the primary focus is on FBLD, many of the lessons also apply to more established approaches such as high-throughput screening. © 2013 Elsevier Ltd. All rights reserved.


Erlanson D.A.,Carmot Therapeutics, Inc.
Topics in Current Chemistry | Year: 2012

Fragment-based drug discovery (FBDD) has emerged in the past decade as a powerful tool for discovering drug leads. The approach first identifies starting points: very small molecules (fragments) that are about half the size of typical drugs. These fragments are then expanded or linked together to generate drug leads. Although the origins of the technique date back some 30 years, it was only in the mid-1990s that experimental techniques became sufficiently sensitive and rapid for the concept to be become practical. Since that time, the field has exploded: FBDD has played a role in discovery of at least 18 drugs that have entered the clinic, and practitioners of FBDD can be found throughout the world in both academia and industry. Literally dozens of reviews have been published on various aspects of FBDD or on the field as a whole, as have three books (Jahnke and Erlanson, Fragment-based approaches in drug discovery, 2006; Zartler and Shapiro, Fragment-based drug discovery: a practical approach, 2008; Kuo, Fragment based drug design: tools, practical approaches, and examples, 2011). However, this chapter will assume that the reader is approaching the field with little prior knowledge. It will introduce some of the key concepts, set the stage for the chapters to follow, and demonstrate how X-ray crystallography plays a central role in fragment identification and advancement. © 2011 Springer-Verlag Berlin-Heidelberg.


Erlanson D.A.,Carmot Therapeutics, Inc.
Journal of Medicinal Chemistry | Year: 2015

Chemical probes are important both as tools to understand biology and as starting points for drug leads, but not every active molecule makes a good probe; many react nonspecifically with thiols. These promiscuous inhibitors are worse than useless because they can mislead researchers and muddy the literature. Understanding the mechanisms of such compounds can prevent scientists from following false hits down blind alleys. © 2015 American Chemical Society.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 500.00K | Year: 2011

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.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 541.53K | Year: 2012

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.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 299.31K | Year: 2010

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.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: SMALL BUSINESS PHASE II | Award Amount: 1.12M | Year: 2011

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.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 200.00K | Year: 2010

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.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 299.81K | Year: 2011

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.


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