A chemoenzymatic technology for the efficient synthesis of novel cryptophycins

Alluvium Biosciences, Inc., Ann Arbor MI

Investigators

Abstract

DESCRIPTION (provided by applicant): The cryptophycins are a structurally diverse class of polyketide/non-ribosomal peptide natural products that possess potent anticancer activity. However, despite this impressive activity, the development of the cryptophycins into a beneficial cancer chemotherapeutic agent has suffered from clinically significant neurotoxicity that correlates with treatment. Nonetheless, the promising therapeutic spectrum of this natural product has motivated Acera Biosciences Inc. to pursue the discovery and development of a cryptophycin compound that that can re-enter clinical evaluation. Within this discovery effort, the company seeks to generate large, structurally diverse libraries of cryptophycin compounds for subsequent biological activity screening. Due to the complex chemical structure of the cryptophycin natural products, which features multiple stereocenters, a macrolactone ring, and a reactive 2-epoxide moiety, the generation of these compounds by traditional synthetic methods requires multiple steps, resulting in low overall yields and a high cost per compound. As such, these methods are not amenable to the rapid production of structurally diverse compounds. Accordingly, in this Phase I STTR proposal, Acera will develop a novel high throughput synthetic technology that will enable access to a diversity of cryptophycin analogues that can be rapidly screened for desirable pharmacological properties. This innovative synthetic platform seeks to utilize routine solid-phase synthesis for the construction of compound libraries containing linear cryptophycin intermediates. The hallmark of the proposed strategy involves chemoenzymatic transformation of the linear cryptophycin intermediates into mature, macrocyclic cryptophycin analogues. In particular, Acera Biosciences Inc. seeks to leverage the catalytic power of the cryptophycin thioesterase (Crp TE) and the cryptophycin epoxidase (CrpE) to specifically and efficiently transform the resin-bound intermediates to macrocyclic compounds bearing the key epoxide functional group. To establish the feasibility of this approach, this proposed research aims to incorporate structural diversity into the 3-chloro-O-methyl-tyrosyl cryptophycin synthon via substitution with 18 commercially available phenylalanine analogues. The resulting 18 novel cryptophycin compounds will be screened for anti-tumor activity and neurotoxicity using a multi-faceted preclinical drug development paradigm developed at Henry Ford Health System. A key feature of this strategy is that small quantities of compounds are required to identify an initial lead compound, making it an ideal complement to the high throughput chemoenzymatic production of cryptophycin analogues. Once proof-of-concept is established, research efforts in Phase II will apply this technology toward the generation of thousands of chemically diverse cryptophycin compounds that will be screened for desirable pharmacological activity. Identified lead compounds can then be licensed to pharmaceutical or biotechnology companies interested in expanding their anti-cancer development programs. PUBLIC HEALTH RELEVANCE: Cancer represents a significant global human health concern that justifies substantial research investments for the discovery and development of novel treatments. Cryptophycin is a known, potent anti-cancer compound that has been dropped from clinical testing due to intolerable side-effects. This proposed research seeks to develop a novel technology for the rapid generation of cryptophycin analogues that may display fewer side effects, thereby enabling cryptophycin to be utilized by physicians in the battle against this often deadly disease.