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.
Most pharmaceutical companies search for new drugs by screening "libraries" of millions of chemical compounds. Because these compounds are derived from previous drug-discovery efforts, they may not contain ideal compounds for newer, more-difficult projects. Carmot Therapeutics is developing Chemotype Evolution, a technology that can search for drugs more efficiently. The technology takes advantage of molecular fragments known to interact with a drug target and then rapidly expands these fragments into new drug leads. Chemotype Evolution can cover more chemical diversity than is currently represented in screening libraries. Thus the technology can accelerate the discovery process and provide access to new chemical diversity, which will be critical for tackling unusual target classes. Carmot’s technology, Chemotype Evolution, both identifies fragments and expands them into a diverse range of hits. The process starts with the selection of an anchor fragment or "bait" that binds to the target of interest and is modified with a reactive functionality for linking to Carmot’s fragment collection. The bait can be derived from existing information (known inhibitors, substrates, or co-factors) or discovered using fragment screening approaches. Carmot has developed a screening platform that can quickly link baits with thousands of molecular fragments to produce custom-made, target-specific screening libraries. Hits identified during a screen can be advanced through traditional medicinal chemistry approaches or used to generate baits for a second screening iteration. A full cycle of bait synthesis, fragment assembly, screening, and hit follow-up can be completed within weeks. Unlike traditional high-throughput screening, where a static library is screened once against a given target, each cycle of Chemotype Evolution creates a new chemical library. By performing sequential cycles of Chemotype Evolution, a single fragment can be converted into diverse and novel lead molecules. In fact, these lead molecules can essentially evolve under selection pressure through iterative cycles of linking and screening. This selection pressure can be applied between each cycle to bias the selection of fragments and baits towards combinations that afford desired properties, such as specificity or cell permeability. This project applies Chemotype Evolution to a general challenge for drug discovery: how to turn peptides into promising small-molecule leads. Peptides can be identified against a wide variety of important disease targets that have generally been deemed intractable for small molecule drugs. While Chemotype Evolution has been successfully applied using small-molecule baits, it had not been explored using peptides or peptide fragments as baits until the research conducted in this proposal. In this project, Carmot has shown that peptides can be deconstructed into baits that are suitable for performing Chemotype Evolution. The goal is now to use Chemotype Evolution to convert these peptide-based baits into drug-like molecules with superior pharmaceutical properties. By creating a systematic and efficient technology to convert peptides into small molecules, Chemotype Evolution provides a new way to address important disease targets. This project has focused on using Chemotype Evolution to generate lead molecules that inhibit the interaction between p53 and HDM2, an interaction that is essential for cancer cell survival and drug resistance but has been a major challenge for conventional drug discovery technologies. Leads from Chemotype Evoution could ultimately result in new cancer therapeutics.
