Novel antifibrotic target related to RhoA-induced MRTF activation in fibrotic diseases

Abstract

Current drug discovery efforts for fibrotic diseases mostly target well-established receptors in pro-fibrotic signaling pathways. However, efficacy remains poor, perhaps due to the redundancy in the signaling pathways. Gene transcription mechanisms are critical control points for cell function as well as disease pathology. It has remained difficult to target gene transcription mechanisms with small molecule drugs due in part to the role of protein-protein interactions in transcription complexes. One such transcription mechanism that plays a critical role in cancer and fibrotic mechanisms is RhoA/C-GTPase regulation of the serum responsive transcription factor complex of serum response factor (SRF) and myocardin-related transcription factor (MRTF).

As a potential anti-fibrotic approach, we undertook a high-throughput screen for Rho/MRTF pathway inhibitor compounds identifying CCG-1423. That compound and its analogs (e.g. CCG-203971) have been used extensively to disrupt myofibroblast activation and tissue fibrosis in multiple in vivo models as well as showing strong activity on melanoma cell migration and metastasis. A critical question, however, is the molecular mechanism and direct protein target of these compounds. Using immobilized compounds and mass spectroscopy, we have now identified the molecular target of the CCG-203971 series. It is a poorly studied intranuclear protein that participates in gene transcription regulation of multiple mechanisms including NF-κ-B and MRTF/SRF. This dual mechanism rationalizes the strong efficacy of CCG-203971 and related compounds as anti-fibrotic and anti-metastatic agents. The identification of this new molecular target for antifibrotic drug development and should facilitate future compound optimization through structure-based drug discovery and target biology evaluation.

Supported by NIH grants R01 AR066049 (to S.D.Larsen) and R01 GM115459 (to R.R.N.)