1. Academic Validation
  2. Targeting the TGF-β receptor with kinase inhibitors for scleroderma therapy

Targeting the TGF-β receptor with kinase inhibitors for scleroderma therapy

  • Arch Pharm (Weinheim). 2014 Sep;347(9):609-15. doi: 10.1002/ardp.201400116.
Lin Cong 1 Zhi-Kuan Xia Rong-Ya Yang
Affiliations

Affiliation

  • 1 Department of Dermatology, General Hospital of Beijing Military Command, Beijing, China; Graduate School, Third Military Medical University, Chongqing, China.
Abstract

Scleroderma (systemic sclerosis) is a connective tissue disease that affects various organ systems; the treatment of scleroderma is still difficult and remains a challenge to the clinician. Recently, kinase inhibitors have shown great potential against fibrotic diseases and, specifically, the Transforming Growth Factor-β receptor (TGF-βR) was found as a new and promising target for scleroderma therapy. In the current study, we propose that the large pool of existing kinase inhibitors could be exploited for inhibiting the TGF-βR to suppress scleroderma. In this respect, we developed a modeling protocol to systematically profile the inhibitory activities of 169 commercially available kinase inhibitors against the TGF-βR, from which five promising candidates were selected and tested using a standard kinase assay protocol. Consequently, two molecular entities, namely the PKB inhibitor MK-2206 and the mTOR C1/C2 inhibitor AZD8055, showed high potency when bound to the TGF-βR, with IC50 values of 97 and 86 nM, respectively, which are close to those of the recently developed TGF-βR selective inhibitors SB525334 and LY2157299 (IC50 = 14.3 and 56 nM, respectively). We also performed atomistic molecular dynamics simulations and post-molecular mechanics/Poisson-Boltzmann surface area analyses to dissect the structural basis and energetic properties of intermolecular interactions between the TGF-βR kinase domain and these potent compounds, highlighting intensive nonbonded networks across the tightly packed interface of non-cognate TGF-βR-inhibitor complexes.

Keywords

Kinase inhibitor; Scleroderma; TGF-β receptor.

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