Summary

Acylin Therapeutics is the first company focused on developing inhibitors of cellular acetylation, an enzymatic mechanism fundamental to the molecular pathology of cancer, metabolic disease, and neurodegeneration. Recent discoveries by Acylin founders and other investigators have revealed protein acetylation as a cellular signal transduction regulator potentially as ubiquitous and important as phosphorylation by kinase enzymes. The Company has developed a platform technology to design specific acyltransferase inhibitors based on crystal structures, novel medicinal chemical approaches, and mechanistic understanding. Acylin has prioritized the p300 and CBP histone acetyl transferases [HATs] for initial drug discovery.

Company Profile

• Founded in 2009 by Boston based entrepreneurs Suresh Jain, Ph.D. and Peter DiStefano, Ph.D., along with scientific co-founders Philip A. Cole, M.D., Ph.D. at Johns Hopkins University School of Medicine and Ronen Marmorstein, Ph.D. at the Wistar Institute.
• Established a platform technology to design specific acyltransferase inhibitors based on crystal structures, novel medicinal chemistry approaches, and mechanistic understanding.
• Discovered and optimized two new series of small molecule inhibitors of p300 HAT using X-ray crystal structures and virtual ligand screening, followed by extensive ongoing medicinal chemistry campaigns.
• Assembled a world-class scientific advisory board of acylation biology and chemistry key opinion leaders.

Management

Edward Kesicki, Ph.D. Senior Director, Chemistry. Previously at Infectious Disease Research Institute, ICOS Corporation, Prolinx.

Board of Directors

• Carl Weissman, Chairman & CEO, Accelerator Corporation
• Steven Gillis, Ph.D., Managing Director, ARCH Venture Partners
• Chad Waite, Managing Director, OVP Venture Partners
• Janis Naeve Ph.D., Director, Amgen Ventures
• Thong Le, Managing Director, WRF Capital
• Lee Babiss, Ph.D., Chief Scientific Officer & Executive Vice President Global Lab Services

Technology Overview

Lysine protein acetylation has been classically defined as a post-translational modification regulating nuclear gene transcription and histone metabolism. However, the list of proteins regulated by reversible acetylation in cytoplasmic processes is growing, supporting a role for reversible acetylation in the regulation of cell proliferation, development, differentiation, and metabolism. The enzymes that catalyze the transfer of an acetyl group onto a lysine are termed histone acetyltransferases (HATs), and the enzymes that remove acetyl groups are histone deacetylases (HDACs). These enzymes are activators and repressors of gene transcription and have recently been shown to be important regulators of cell signaling pathways. Major pharmaceutical and biotech companies have shown a keen interest in acetylation technology, with two oncology approved HDAC inhibitors and dozens of additional compounds in clinical trials. Biological studies with knock-out mice and RNAi confirm that HAT inhibitors may be useful for treating cancer, metabolic disorders, and CNS disease. However, identification of HAT inhibitors has proven to be much more difficult: No HAT inhibitors have been identified with sufficient potency and appropriate pharmaceutical characteristics to enter clinical development. Acylin’s founders are the first investigators to crystallize and solve the structure for multiple HAT proteins, and the company has subsequently used this information in virtual screens to identify and optimize the first potent and selective small molecule HAT inhibitors.

The histone acetyltransferase enzymes p300 and CBP are the first drug discovery targets prioritized by Acylin. As the best characterized HATs in the literature, p300 and CBP are transcriptional coactivators implicated in select gene regulatory pathways and protein acetylation events. While weak p300/CBP inhibitors have been reported, a potent, selective, and active-site directed small molecule inhibitor had not been previously described. Acylin has performed in silico screening using the p300 crystal structure data and a virtual compound library of commercial compounds. Several virtual hits were confirmed in p300/CBP biochemical assays and selectivity assays. Extensive medicinal chemistry has led to highly selective and potent molecules with drug-like characteristics in two chemical series. Both series show selectivity for p300/CBP versus other acetyltransferases and inhibit p300/CBP-mediated acetylation in cell-based assays. Acylin is moving forward with in vivo testing of lead compounds and continuing medicinal chemistry to define an initial drug candidate. Acylin technology also represents a platform opportunity, and future high throughput screens will target other HAT family member crystal structures, including PCAF, GCN5, MOZ, and TIP60.

Acylin is the first biotech company focusing exclusively on developing inhibitors of protein acetylation, a post-translational modification important in both transcriptional modulation and cell signaling cascades. Modulating the post-translational acylation of gene products is increasingly being implicated in the molecular pathogenesis of several unmet clinical needs, including oncology and metabolism. Our HAT inhibitor program represents best-in-class effort for new classes of inhibitors based on proprietary technology and know-how exclusive to Acylin.

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