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

Area of Science:

• Pharmacology
• Biochemistry
• Computational Biology

Background:

• Scleroderma (systemic sclerosis) is a challenging connective tissue disease impacting multiple organ systems.
• Current treatments for scleroderma are limited, necessitating novel therapeutic strategies.
• The transforming growth factor-β receptor (TGF-βR) has emerged as a promising therapeutic target for fibrotic diseases like scleroderma.

Purpose of the Study:

• To investigate the potential of existing kinase inhibitors for targeting the TGF-βR in scleroderma therapy.
• To identify potent kinase inhibitors capable of suppressing TGF-βR activity.
• To elucidate the structural and energetic basis of TGF-βR inhibition by selected compounds.

Main Methods:

• Development of a computational protocol to screen 169 commercially available kinase inhibitors against the TGF-βR.
• In vitro kinase assay validation of top-ranked inhibitor candidates.
• Atomistic molecular dynamics simulations and MM/PBSA analyses to study inhibitor-target interactions.

Main Results:

• Five kinase inhibitors were identified as promising candidates for TGF-βR inhibition.
• PKB inhibitor MK-2206 and mTOR inhibitor AZD8055 demonstrated high potency against TGF-βR (IC50 values of 97 nM and 86 nM, respectively).
• Structural and energetic analyses revealed detailed interactions within the TGF-βR kinase domain-inhibitor complexes.

Conclusions:

• Repurposing existing kinase inhibitors is a viable strategy for developing novel scleroderma therapies.
• MK-2206 and AZD8055 represent potent, non-selective TGF-βR inhibitors with potential therapeutic applications.
• Understanding the molecular interactions provides insights for designing more selective and effective TGF-βR inhibitors.