Person:

Cole, Philip

Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes. CoREST knockdown, gene expression, and ChIP studies suggest that corin’s favorable pharmacologic effects may rely on an intact CoREST complex. Corin was also effective in slowing tumor growth in a melanoma mouse xenograft model. These studies highlight the promise of a new class of two-pronged hybrid agents that may show preferential targeting of particular epigenetic regulatory complexes and offer unique therapeutic opportunities.

Coat proteins play a central role in vesicular transport by binding to cargoes for their sorting into intracellular pathways. Cargo recognition is mediated by components of the coat complex known as adaptor proteins. We previously showed that ACAP1 (ArfGAP with Coil-coil Ankyrin repeat Protein 1) functions as an adaptor for a clathrin coat complex acting in endocytic recycling. Here, we find that the protein kinase Akt acts as a co-adaptor in this complex, needed in conjunction with ACAP1 to bind cargo proteins for their recycling. Besides advancing the understanding of endocytic recycling, our findings uncover a fundamentally different way that a kinase acts, being an effector rather than a regulator in a cellular event.