FOXM1 Inhibition by Thiostrepton Derivatives

Mitchell Christy
Appointment Period: 2017-2018, Grant Year: [31, 32]

The disruption of protein-protein and protein-nucleic acid interactions has long been sought for the development of therapeutics for numerous diseases states. However, the interference of these large molecular interactions by small molecules has been largely unsuccessful and theses systems have been deemed to be “undruggable”. One approach has been to employ compounds that are larger than those conventionally used in drug discovery to provide larger surfaces to prevent the required interactions for native function. Given their size natural products provide ideal starting points for this type of discovery process. To this end the anticancer activity of thiosterpton, a thiopeptide natural product, has been traced to its ability to directly interact with a transcription factor. Forkhead box M1 (FOXM1), an oncogenic transcription factor, is targeted by thiostrepton and upon the binding of thiostrepton to FOXM1 the transcriptional activity is blocked. FOXM1 has been characterized as a driver in multiple cancers for progression, angiogenesis, and metastasis. The discovery of new compounds with better physiochemical properties is the next step toward the development of FOXM1 inhibitors with clinical potential.

Given the large molecular architecture and diverse functionality of thiostrepton it is desirable to reduce the compound to a minimal pharmacophore. The minimal pharmacophore includes the key 26- membered macrocycle within thiostrepton. With this approach, starting from a common intermediate, synthetic access to new compounds and probes will be possible through specific modifications.

Our experience synthesizing thiopeptides quickly adapted a useful strategy for the syntheses of the main components, chiral carboxy amino thiazoles. The majority of syntheses of this class of natural products or derivatives heavily utilize the Hantzch thiazole synthesis. This is understandable, the method is highly reliable, however, we have found running these reactions on the multi-decagram scale proved challenging both from the perspective of maintaining yields and purification. As a result we now use two alternative methods for the syntheses of thiazole containing fragments 1) cysteine- nitrile condensation reactions followed by aromatization and 2) addition of thiazole-based Grignard reagents into chiral N-sulfinyl imines. To date, these reactions have provided routes that allow us to access large amounts of fully synthetic derivatives. This has permitted expedited synthesis of the main fragment, accessing the methyl ester derivate in a 15 step synthetic sequence from threonine in amounts that can be used for analog synthesis.

PUBLICATIONS (resulting from this training):

Trainee recently appointed to grant: publications are still in progress.