A diverse range of selective FGFR4 inhibitor hit series were identified using unbiased screening approaches and by the modification of known kinase inhibitor scaffolds. In each case the origin of the selectivity was consistent with an interaction with a poorly conserved cysteine residue within the middle-hinge region of the kinase domain of FGFR4, at position 552. Targeting this region identified a non-covalent diaminopyrimidine series differentiating by size, an irreversible-covalent inhibitor in which Cys552 undergoes an SNAr reaction with a 2-chloropyridine, and a reversible-covalent inhibitor series in which Cys552 forms a hemithioacetal adduct with a 2-formyl naphthalene. In addition, the introduction of an acrylamide into a known FGFR scaffold identified a pan-FGFR inhibitor which reacted with both Cys552 and a second poorly conserved cysteine on the P-loop of FGFR4 at position 477 which is present in all four FGFR family members.
FGF19 signaling through
the FGFR4/β-klotho receptor complex
has been shown to be a key driver of growth and survival in a subset
of hepatocellular carcinomas, making selective FGFR4 inhibition an
attractive treatment opportunity. A kinome-wide sequence alignment
highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding
site at position 552, two positions beyond the gate-keeper residue.
Several strategies for targeting this cysteine to identify FGFR4 selective
inhibitor starting points are summarized which made use of both rational
and unbiased screening approaches. The optimization of a 2-formylquinoline
amide hit series is described in which the aldehyde makes a hemithioacetal
reversible-covalent interaction with cysteine 552. Key challenges
addressed during the optimization are improving the FGFR4 potency,
metabolic stability, and solubility leading ultimately to the highly
selective first-in-class clinical candidate roblitinib.
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and it is the third leading cause of cancer-related deaths worldwide. Recently, aberrant signaling through the FGF19/FGFR4 axis has been implicated in HCC. Here, we describe the development of FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. FGF401 is exquisitely selective for FGFR4 versus the other FGFR paralogues FGFR1, FGFR2, FGFR3, and all other kinases in the kinome. FGF401 has excellent drug-like properties showing a robust pharmacokinetic/pharmacodynamics/efficacy relationship, driven by a fraction of time above the phospho-FGFR4 IC90 value. FGF401 has remarkable antitumor activity in mice bearing HCC tumor xenografts and patient-derived xenograft models that are positive for FGF19, FGFR4, and KLB. FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a phase I/II study is currently ongoing in HCC and other solid malignancies.
Mutations in the gene for the transforming growth factor (TGF)- superfamily receptor, bone morphogenetic protein receptor II, underlie heritable forms of pulmonary arterial hypertension (PAH). Aberrant signaling via TGF- receptor I/activin receptor-like kinase 5 may be important for both the development and progression of PAH. We investigated the therapeutic potential of a well-characterized and potent activin receptor-like kinase 5 inhibitor, SB525334 ͓6-(2-tert-butyl-5-{6-methyl-pyridin-2-yl}-1H-imidazol-4-yl)-quinoxaline͔ for the treatment of PAH. In this study, we demonstrate that pulmonary artery smooth muscle cells from patients with familial forms of idiopathic PAH exhibit heightened sensitivity to TGF-1 in vitro, which can be attenuated after the administration of SB525334. We further demonstrate that SB525334 significantly reverses pulmonary arterial pressure and inhibits right ventricular hypertrophy in a rat model of PAH. Immunohistochemical studies confirmed a significant reduction in pulmonary arteriole muscularization induced by monocrotaline Pulmonary arterial hypertension (PAH) is a severe disease of the small pulmonary arteries characterized by vascular damage and narrowing of the vessels, leading to raised pulmonary artery pressure, right ventricular (RV) hypertrophy, and ultimately, right-sided heart failure and death. The combined effects of vasoconstriction, remodeling of the pulmonary vessel wall comprising abnormal endothelial and pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis, enhanced extracellular matrix deposition, and elevated thrombosis contribute to increased pulmonary vascular resistance and the resultant right-sided cardiac hypertrophy and mortality. Although the exact molecular basis underlying the vascular damage remains unclear, genetic studies have linked germ-line mutations in a gene encoding the transforming growth factor  (TGF-) superfamily receptor member bone morphogenetic protein receptor 2 (BMPR-II) to the development of heritable forms of idiopathic pulmonary arterial hypertension (iPAH), encompassing familial and a proportion of sporadic cases of the disease.
Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRAS G12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique, covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRAS G12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRAS G12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with SHP2, MEK or CDK4/6 inhibitors. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRAS G12C-mutated tumors.
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