title: Targeting the TGF-β receptor with kinase inhibitors for scleroderma therapy.
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.
authors.affiliation: Department of Dermatology, General Hospital of Beijing Military Command, Beijing, China; Graduate School, Third Military Medical University, Chongqing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cong
authors.forename: Zhi-Kuan
authors.initials: ZK
authors.lastname: Xia
authors.forename: Rong-Ya
authors.initials: RY
authors.lastname: Yang
mesh_terms: D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism
chemical_list: C521813:6-(2-tert-butyl-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline; D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; C548887:MK 2206; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D011810:Quinoxalines; D018125:Receptors, Transforming Growth Factor beta; C557799:LY-2157299; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
keywords: Kinase inhibitor; Scleroderma; TGF-β receptor