ABSTRACT
FGF19 signaling through the FGFR4/ß-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.
Subject(s)
Piperazines/chemistry , Protein Kinase Inhibitors/chemistry , Pyridines/chemistry , Receptor, Fibroblast Growth Factor, Type 4/antagonists & inhibitors , Amino Acid Sequence , Animals , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Cysteine/chemistry , Dogs , Drug Design , Half-Life , Hepatocytes/cytology , Hepatocytes/drug effects , Hepatocytes/metabolism , Liver Neoplasms/drug therapy , Mice , Microsomes, Liver/metabolism , Molecular Dynamics Simulation , Piperazines/metabolism , Piperazines/pharmacology , Piperazines/therapeutic use , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyridines/metabolism , Pyridines/pharmacology , Pyridines/therapeutic use , Rats , Receptor, Fibroblast Growth Factor, Type 4/metabolism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A cyclisation within a 4',5-bisthiazole (S)-proline-amide-urea series of selective PI3Kα inhibitors led to a novel 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole tricyclic sub-series. The synthesis and optimisation of this 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole sub-series and the expansion to a related tricyclic 4,5-dihydrothiazolo[4,5-h]quinazoline sub-series are described. From this work analogues including 11, 12, 19 and 23 were identified as potent and selective PI3Kα inhibitor in vivo tool compounds.
Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , Animals , Caco-2 Cells , Class I Phosphatidylinositol 3-Kinases , Female , Humans , Mice, Nude , Models, Molecular , Neoplasms/drug therapy , Neoplasms/enzymology , Phosphatidylinositol 3-Kinases/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Quinazolines/pharmacokinetics , Quinazolines/therapeutic use , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/therapeutic useABSTRACT
Exploring the affinity-pocket binding moiety of a 2-aminothiazole (S)-proline-amide-urea series of selective PI3Kα inhibitors using a parallel-synthesis approach led to the identification of a novel 4',5-bisthiazole sub-series. The synthesis and optimisation of both the affinity pocket and (S)-proline amide moieties within this 4',5-bisthiazole sub-series are described. From this work a number of analogues, including 14 (A66) and 24, were identified as potent and selective PI3Kα inhibitor in vitro tool compounds.
