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Acpharis Awarded SBIR for Development of Covalent Fragments

Covalent drugs represent a significant portion of current pharmaceuticals, with the top 26 having sales of over $30B in the US alone. While in the past target-directed drug discovery projects rarely pursued covalent binders due to safety concerns, the industry is increasingly investing in the use of targeted covalent inhibitors (TCIs) that utilize soft reactive warheads, weak electrophiles that become locally reactive only in the context of the topology of a binding site.
Developing a TCI requires a potent and specific reversible scaffold and the ability to covalently bind it to a selective group, most frequently a cysteine side chain. For example, Avila Therapeutics (acquired by Celgene) has developed tools for the efficient design of covalent inhibitors starting from known reversible inhibitors. However, for many targets there exist no appropriate starting compounds, and it is desirable to develop a more general design methodology.
In this Phase I SBIR, Acpharis plans to develop algorithms and software for the efficient design of covalent inhibitors that will be based on well-established principles of fragment based drug discovery. Introducing this new approach will expand the design of covalent inhibitors to new classes of targets such as inhibition of protein-protein interactions. Acpharis has developed novel computational tools for fragment based drug design that will be extended to the design of covalent inhibitors. In addition to validating the method on targets that have known covalent inhibitors, we will seek covalent hits for the protein-protein interaction target KEAP1, with compounds to be tested in the laboratory of Dr. Adrian Whitty at Boston University.