Process Chemistry of Largazole, a Marine HDAC Inhibitor with Anticancer Activity

DESCRIPTION provided by applicant Significance Colorectal cancer CRC remains an unmet need and is a significant challenge to the healthcare system as one of the leading forms of cancer in the United States affecting an estimated people and causing an estimated deaths in Estimates of base case for the medical care costs for colorectal cancer in were $ billion and it is projected to increase to $ billion by Largazole is
a differentiated novel class I selective histone deacetylase HDAC inhibitor derived from a marine cyanobacterium that shows selective anticancer activity both in vitro and in vivo Hypothesis Our overall hypothesis is that largazole is an effective novel therapeutic agent for metastatic and or refractory CRC and potentially other refractory solid tumors To support clinical development we first need to synthesize sufficient quantities of largazole and develop a
more robust method for large scale synthesis amenable to subsequent manufacture Completion of this Phase I SBIR goal will allow us to focus on future preclinical studies to test this hypothesis in Phase II Preliminary Data The NCI screen showed largazole to be highly active against colon cancer cells and it modulated gene expression induced cell cycle inhibitors such as p and downregulated cancer associated receptor tyrosine kinases RTKs resulting in concentration dependent cell cycle arrest and apoptosis Largazole was efficacious in HCT colon tumor xenograft mouse model retarding tumor growth without acute toxicity at intraperitoneal doses up to mg kg In an in vivo breast cancer model of highly invasive MDA MB cells representing triple negative breast cancer largazole combined with dexamethasone reduced the invasiveness of cancer cells by mediating cell cell contacts i e prevented cell movement and metastasis In addition to its in vivo anticancer and anti invasive properties largazole showed bone forming activity in mouse and rabbit in vivo models and it reduced CCl induced liver fibrosis Specific Aims Largazole preclinical evaluations formulation development and subsequent clinical trials requires a scalable synthetic method to produce larger amounts of material In Aim we will focus on the synthesis of some of the key building blocks of largazole Specifically we will evaluate the synthesis of thioacid thioester R methyl cysteine Boc protected aminomethyl cyano thiazole and alcohol In Aim we will conduct process chemistry research to improve the yields of the two final steps of largazole synthesis focused on the macrocyclization and cross metathesis reactions The identity and purity of all compounds will be verified by NMR and mass spectrometry We expect that we will be able to produce adequate quantities of key building blocks and improve the yields of the last two steps of synthesis to approximately allowing a significant improvement in the yield of largazole through this novel scalable synthetic method to provide material for preclinical studies to be pursued in a Phase II proposal and eventual clinical development of largazole

PUBLIC HEALTH RELEVANCE Colorectal cancer CRC is a significant challenge to the healthcare system as one of the leading forms of cancer in the United States affecting an estimated people and causing an estimated deaths in Largazole a selective class I histone deacetylase HDAC inhibitor has shown excellent activity against colorectal cancer models in preclinical studies potentially providing a new targeted therapeutic approach to treating refractory and or metastatic colorectal cancer with largazole alone or in combination with other anticancer drugs This proposed SBIR Phase I grant will complete a larger scale synthesis of largazole to enable in Phase II the conduct of additional preclinical studies and development of formulations suitable for human use to advance this novel drug candidate into colorectal cancer patients