Are there any selective small molecule inhibitors of FGFR4?
HCC is a devastating disease with limited treatment options. Here, we present data suggesting that a potent and selective FGFR4 inhibitor, such as BLU9931, might be an effective therapy for the subset of patients with HCC whose tumors are driven by aberrant FGFR4 signaling in response to autocrine FGF19 stimulation.
What happens when FGFR4 is activated by FGF19?
Downstream signaling, upon activation of FGFR4 by FGF19, leads to the inhibition of hepatic enzyme cholesterol 7α-hydroxylase (CYP7A1) expression, resulting in reduced bile acid synthesis ( 6 ). This activation of FGFR4 by FGF19 requires the cofactor KLB, which is normally bound to FGFR4 ( 7 ).
Are there any pan FGFR inhibitors for HCC?
While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1-3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design.
How does FGF19 inhibit bile acid synthesis in the liver?
FGF19 is a gut-secreted endocrine hormone that acts in the liver through the receptor tyrosine kinase FGFR4 to regulate bile acid synthesis (6). Downstream signaling, upon activation of FGFR4 by FGF19, leads to the inhibition of hepatic enzyme cholesterol 7α-hydroxylase (CYP7A1) expression, resulting in reduced bile acid synthesis (6).
Where are the cysteines located in FGFR4?
FGFR4 contains two cysteines proximal to its ATP-binding pocket ( 19 ). One, Cys478, located at the tip of the P-loop, is conserved among all FGFR paralogs, and has been successfully targeted by a covalent FGFR pan-inhibitor ( 21 ).
Which is the best treatment for FGFR signalling?
Small-molecule kinase inhibitors are, thus far, the most widely used therapeutic approach to inhibition of FGFR signalling in patients with cancer 19, 20, 21.
Can a FGFR4 inhibitor be used for HCC?
Approximately one third of patients with HCC whose tumors express FGF19 together with FGFR4 and its coreceptor klotho β ( KLB) could potentially respond to treatment with an FGFR4 inhibitor. These findings are the first demonstration of a therapeutic strategy that targets a subset of patients with HCC.