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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. Source

Murray C.W.,Astex | Erlanson D.A.,Carmot Therapeutics, Inc. | Hopkins A.L.,University of Dundee | Keseru G.M.,Hungarian Academy of Sciences | And 4 more authors.
ACS Medicinal Chemistry Letters | Year: 2014

A recent viewpoint article (Improving the plausibility of success with inefficient metrics. ACS Med. Chem. Lett. 2014, 5, 2-5) argued that the standard definition of ligand efficiency (LE) is mathematically invalid. In this viewpoint, we address this criticism and show categorically that the definition of LE is mathematically valid. LE and other metrics such as lipophilic ligand efficiency (LLE) can be useful during the multiparameter optimization challenge faced by medicinal chemists. © 2014 American Chemical Society. Source

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. Source

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. Source

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.

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