title: SAR103168: a tyrosine kinase inhibitor with therapeutic potential in myeloid leukemias.
abstract: SAR103168, a tyrosine kinase inhibitor of the pyrido [2,3-d] pyridimidine subclass, inhibited the kinase activities of the entire Src kinase family, Abl kinase, angiogenic receptor kinases (vascular endothelial growth factor receptor [VEGFR] 1 and 2), Tie2, platelet derived growth factor (PDGF), fibroblast growth factor receptor (FGFR) 1 and 3, and epidermal growth factor receptor (EGFR). SAR103168 was a potent Src inhibitor, with 50% inhibitory concentration (IC50) = 0.65 ± 0.02 nM (at 100 μM ATP), targeting the auto-phosphorylation of the kinase domain (Src(260-535)) and activity of the phosphorylated kinase. Phosphorylation of Src, Lyn and Src downstream signaling pathways (PYK2, P-130CAS, FAK, JNK and MAPK) were inhibited in a dose-dependent manner. SAR103168 inhibited the phosphorylation of STAT5 in KG1 cells and fresh cells from patients with acute myeloid leukemia (AML). SAR103168 inhibited proliferation and induced apoptosis in acute and chronic myeloid leukemic cells at nanomolar IC50. SAR103168 induced anti-proliferation of leukemic progenitors (CFU-L) from 29 patients with AML, and > 85% of AML patient samples were sensitive to SAR103168. These antagonist activities of SAR103168 were independent of FLT3 expression. SAR103168 treatment was effective in 50% of high-risk patient samples carrying chromosome 7 abnormalities or complex rearrangement. SAR103168 administration (intravenous or oral) impaired tumor growth and induced tumor regression in animals bearing human AML leukemic cells, correlating with potent inhibition of Src downstream signaling pathways in AML tumors. SAR103168 showed potent anti-tumor activity in SCID (severe combined immunodeficiency) mice bearing AML (KG1, EOL-1, Kasumi-1, CTV1) and chronic myeloid leukemia (CML) (K562) tumors. The combination of cytarabine and SAR103168 showed synergistic activity in AML and CML tumor models. These results highlight the therapeutic potential of SAR103168 in myeloid leukemias and support the rationale for clinical investigations.
authors.affiliation: Formerly Sanofi, Montpellier, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Bourrié
authors.forename: Diana L
authors.initials: DL
authors.lastname: Brassard
authors.forename: Sylvie
authors.initials: S
authors.lastname: Cosnier-Pucheu
authors.forename: Asher
authors.initials: A
authors.lastname: Zilberstein
authors.forename: Kin
authors.initials: K
authors.lastname: Yu
authors.forename: Mikhail
authors.initials: M
authors.lastname: Levit
authors.forename: J Gil
authors.initials: JG
authors.lastname: Morrison
authors.forename: Pierre
authors.initials: P
authors.lastname: Perreaut
authors.forename: Samir
authors.initials: S
authors.lastname: Jegham
authors.forename: Sandrine
authors.initials: S
authors.lastname: Hilairet
authors.forename: Monsif
authors.initials: M
authors.lastname: Bouaboula
authors.forename: Geraldine
authors.initials: G
authors.lastname: Penarier
authors.forename: Cécile
authors.initials: C
authors.lastname: Guiot
authors.forename: Philippe
authors.initials: P
authors.lastname: Larroze-Chicot
authors.forename: Guy
authors.initials: G
authors.lastname: Laurent
authors.forename: Cécile
authors.initials: C
authors.lastname: Demur
authors.forename: Pierre
authors.initials: P
authors.lastname: Casellas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C586184:SAR103168; D020794:Receptor Protein-Tyrosine Kinases; D019061:src-Family Kinases