SSR 128129 / Sanofi - LARVOL DELTA

Differential effects of the N-terminal helix of FGF8b on the activity of a small-molecule FGFR inhibitor in cell culture and for the extracellular domain of FGFR3c in solution. (PubMed, FEBS Lett) - "SSR128129E (SSR) is a unique small-molecule inhibitor of fibroblast growth factor receptors (FGFRs)...On the other hand, when studied in the context of separate extracellular domains of FGFR3c in solution with NMR spectroscopy, SSR is unable to displace the N-terminal helix of FGF8b from its binding site on FGFR3c and behaves as a weak orthosteric inhibitor. The substantial inconsistency between the results obtained with cell culture and for the individual water-soluble subdomains of the FGFR proteins points to the important role played by the cell membrane."

Journal • Preclinical • FGF2

FGFR1+ cancer associated fibroblasts (CAFs) produce an extracellular matrix (ECM) that curbs infiltration of phagocytic tumor-associated macrophages (TAMs). (AACR 2024) - "Accordingly, no anti-tumoral effect was detected when the selective FGFR1i SSR128129E was administered in vitro to a lymphoma cell panel...Consequent with these findings we not only observed an increase infiltration of TAMs in the LME of FGFR1i tumors but also that they were reprogrammed in phagocytic phenotypes. In sum, our results suggest that CAF-FGFR1+ produce an immune "silent" ECM that characterizes RR-DLBCL while FGFR1i reverses this ECM phenotype ultimately resulting in the infiltration of antitumoral TAMs, delineating a novel ECM-directed therapeutic approach for this disease."

Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CAFs • CCL2 • CXCL12 • CXCL3 • FGFR1 • IL16 • IL6 • LUM • TNFA • TP53

FGFR1 Is a Novel Therapeutic Target in Relapsed/Refractory Diffuse Large B Cell Lymphoma (RR-DLBCL) (ASH 2022) - "We then tested the anti-lymphoma effect of the novel selective oral FGFR1 inhibitor SSR128129E (FGFR1i) in two engrafted syngeneic mouse models DLBCL (A20 and Setd2+/-/Bcl2OE) implanted subcutaneously and intrasplenically, respectively, in immunocompetent mice...To test this notion, we assessed the effect of FGFR1i in a murine lymphoma model depleted of macrophages using liposomal clodronate...In conclusion, our results suggest that CAFFGFR1s could constitute a novel LME-resident therapeutic vulnerability in RR-DLBCL and that FGFR1i may require phagocytic TAMs for its anti-lymphoma effect. Given the FDA approval of several FGFR1/2 inhibitors for solid tumors, our results bare translational potential to benefit RR-DLBCL patients in the near term."

IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • BCL2 • BCL6 • CAFs • CCL2 • CXCL12 • CXCL3 • FGFR1 • PDX1 • SETD2

FGF2 positively regulates osteoclastogenesis via activating the ERK-CREB pathway. (PubMed, Arch Biochem Biophys) - "The FGF receptor (FGFR) allosteric antagonist SSR128129E modestly, whereas the FGFR tyrosine kinase inhibitor AZD4547 significantly antagonized the effects of FGF2. Mechanistically, FGF2 stimulated ERK phosphorylation, and the ERK signaling inhibitor PD325901 strongly blocked FGF2 enhancement of osteoclastogenesis...In conclusion, FGF2 positively regulates osteoclastogenesis via stimulating the ERK-CREB pathway. These findings establish the importance of FGF2 in bone homeostasis, hinting the potential use of FGF2/ERK/CREB specific inhibitors to fight against bone-related disorders, such as osteoporosis."

Journal • Osteoporosis • Rheumatology • FGF2 • FGFR

The fibroblast growth factor receptor antagonist SSR128129E inhibits fat accumulation via suppressing adipogenesis in mice. (PubMed, Mol Biol Rep) - "SSR may be a promising drug candidate for the prevention of obesity via suppressing adipogenesis. However, the influence of SSR on thermogenesis in humans should be further investigated before its clinical application."

Journal • Preclinical • Genetic Disorders • Obesity • FGFR