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4years
Structure-Based Virtual Screening, Molecular Dynamics and Binding Free Energy Calculations of Hit Candidates as ALK-5 Inhibitors. (PubMed, Molecules)
ALK-5 inhibitors, such as SB505154, GW6604, SD208, and LY2157299, have recently been reported to inhibit ALK-5 autophosphorylation and induce the transcription of matrix genes. From a lead-like subset of purchasable compounds, five molecules were identified as putative ALK-5 inhibitors. In addition, molecular dynamics and binding free energy calculations combined with pharmacokinetics and toxicity profiling demonstrated the suitability of these compounds to be further investigated as novel ALK-5 inhibitors.
Journal
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ALK (Anaplastic lymphoma kinase)
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galunisertib (LY2157299) • SD 093 • SD 208
4years
TGFβ inhibition stimulates collagen maturation to enhance bone repair and fracture resistance in a murine myeloma model. (PubMed, J Bone Miner Res)
Using in vivo μCT we show substantial and rapid bone lesion repair (and prevention) driven by SD-208 (TGFβ receptor I kinase inhibitor) and chemotherapy (bortezomib and lenalidomide) in mice with human U266-GFP-luc myeloma. We also discovered that SD-208 promoted osteoblastic differentiation (and overcame the TGF?-induced block in osteoblastogenesis) in myeloma patient bone marrow stromal cells in vitro, comparable to normal donors. The improved bone quality and fracture-resistance with SD-208 provides incentive for clinical translation to improve myeloma patient quality of life by reducing fracture risk and fatality.
Preclinical • Journal
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VEGFA (Vascular endothelial growth factor A)
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lenalidomide • bortezomib • SD 093 • SD 208
over4years
Inhibition of TGF-β-receptor signaling augments the antitumor function of ROR1-specific CAR T-cells against triple-negative breast cancer. (PubMed, J Immunother Cancer)
We demonstrate the TGF-β suppresses the antitumor function of ROR1-CAR T-cells against TNBC in preclinical models. Our study supports the continued preclinical development and the clinical evaluation of combination treatments that shield CAR T-cells from TGF-β, as exemplified by the TGF-β-receptor kinase inhibitor SD-208 in this study.
Journal • CAR T-Cell Therapy • PD(L)-1 Biomarker
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CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • SMAD4 (SMAD family member 4)
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PD-1 expression
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SD 093 • SD 208