ABL inhibitors(Abl family tyrosine kinases inhibitors), EGFR antagonists(Epidermal growth factor receptor erbB1 antagonists), FGFR1 antagonists(Fibroblast growth factor receptor 1 antagonists)

+ [6]

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication-

Inactive Indication

acute leukemiaAcute Myeloid LeukemiaMyelodysplastic Syndromes

Originator Organization

Sanofi

Active Organization-

Inactive Organization

Sanofi

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

Structure

Molecular FormulaC24H20Cl2N8OS

InChIKeyUARVFMMJGJJSNR-UHFFFAOYSA-N

CAS Registry918106-11-3

Clinical Trials associated with SAR-103168

NCT00981240 / CompletedPhase 1

A Dose Escalation Safety and Pharmacokinetic Study of SAR103168 Administered as a Single Agent by Intravenous Infusion, Once Daily for 5 Consecutive Days to Patients With Refractory/ Relapsed Acute Leukemias or High-risk Myelodysplastic Syndromes.

Primary objectives:
To determine the maximum tolerated dose (MTD) of SAR103168 and to characterize the dose limiting toxicities (DLTs) in the proposed dose regimen
To evaluate the pharmacokinetic (PK) profile of SAR103168
Secondary objectives:
To characterize the global safety profile of SAR103168
To evaluate preliminary anti-leukemia activity
To investigate the potential induction effect on CYP3A4 and persistence of this effect by using oral midazolam as a probe substrate in patients enrolled into the expanded cohort at the MTD
To determine the metabolic pathways of SAR103168 and identify the chemical structures of metabolites
To determine the potential impact of SAR103168 on the QTc interval in patients enrolled at the MTD

Start Date01 Sep 2009

Sponsor / Collaborator

Sanofi

100 Clinical Results associated with SAR-103168

100 Translational Medicine associated with SAR-103168

100 Patents (Medical) associated with SAR-103168

Literatures (Medical) associated with SAR-103168

01 Feb 2015·Leukemia & LymphomaQ4 · MEDICINE

Phase I trial of SAR103168, a novel multi-kinase inhibitor, in patients with refractory/relapsed acute leukemia or high-risk myelodysplastic syndrome

Q4 · MEDICINE

Article

Author: H. Jean Khoury ; Eric J. Feldman ; Harry Miao ; Martha Arellano ; Ellen K. Ritchie ; Wilena Session ; Wei Zheng ; Stefan Faderl ; Elias Jabbour ; Farhad Ravandi ; Gail J. Roboz ; J. Gilmour Morrison

There is no effective treatment for relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We conducted a phase I dose escalation trial of SAR103168, a novel multi-targeted kinase inhibitor with activity against the Src kinase family, the BCR-Abl kinase and several angiogenic receptor kinases. Twenty-nine patients 18-83 years old were treated with SAR103168. Pharmacokinetics was characterized by plasma peak concentration (Cmax) at the end of the infusion, followed by a biphasic decline in the elimination profile. Adverse events were as expected for the patient population and there were no individual toxicities specific to SAR103168. Due to the unpredictable nature of drug exposure, the sponsor decided to discontinue the study prior to reaching the maximum tolerated dose.

01 Jul 2013·Leukemia & LymphomaQ4 · MEDICINE

SAR103168: a tyrosine kinase inhibitor with therapeutic potential in myeloid leukemias

Q4 · MEDICINE

Article

Author: Bourrié, Bernard ; Demur, Cécile ; Larroze-Chicot, Philippe ; Morrison, J. Gil ; Bouaboula, Monsif ; Casellas, Pierre ; Yu, Kin ; Jegham, Samir ; Perreaut, Pierre ; Cosnier-Pucheu, Sylvie ; Zilberstein, Asher ; Guiot, Cécile ; Hilairet, Sandrine ; Penarier, Geraldine ; Brassard, Diana L. ; Laurent, Guy ; Levit, Mikhail

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.

100 Deals associated with SAR-103168

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
acute leukemia	Phase 1	US	Sanofi	01 Sep 2009
Acute Myeloid Leukemia	Phase 1	US	Sanofi	01 Sep 2009
Myelodysplastic Syndromes	Phase 1	US	Sanofi	01 Sep 2009

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