CEP-40783  (Synonyms: RXDX-106)

CEP-40783 is a potent, selective and orally available inhibitor of AXL and c-Met with IC₅₀ values of 7 nM and 12 nM, respectively.

In AXL-transfected 293GT cells, CEP-40783 is 27-fold more active compared to recombinant enzyme with an IC₅₀ value of 0.26 nM. CEP-40783 also demonstrates superior activity against c-Met in GTL-16 cells (IC₅₀=6 nM). The increased inhibitory activity of CEP-40783 in cells could be attributed to its extended residence time on both AXL and c-Met, consistent with a Type II mechanism. CEP-40783 shows high kinome selectivity against 298 kinases with an S90 of 0.04 (fraction of kinases showing >90% inhibition at 1 μM)^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

CEP-40783 shows dose- and time-dependent inhibition of AXL phosphorylation using NCI-H1299 NSCL xenografts with 80% target inhibition at 0.3 mg/kg 6 h post dose and complete target inhibition to >90% inhibition at 1 mg/kg between 6-24 h, while a 10 mg/kg po dose resulted in complete AXL inhibition up to 48 h post dosing^[1]. In 3/5 (60%) of the tumor models, CEP-40783 shows in vivo efficacy, including tumor regressions, significantly superior to that achieved with an optimal regimen of paclitaxel. In 4/4 (100%) of the erlotinib-insensitive tumor models, CEP-40783 demonstrates significant efficacy (66 to 118% TGI) compared to the control group at the 30 mg/kg dose. Additionally, CEP-40783 in combination with erlotinib demonstrate superior anti-tumor efficacy compared to CEP-40783 and erlotinib single agents in the one erlotinib-sensitive model evaluated. CEP-40783 as a single agent and in combination with erlotinib are well tolerated^[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

588.56

C₃₁H₂₆F₂N₄O₆

1437321-24-8

Solid

White to off-white

O=C(C1=CN(C(C)C)C(N(C2=CC=C(F)C=C2)C1=O)=O)NC3=CC=C(OC4=CC=NC5=CC(OC)=C(OC)C=C45)C(F)=C3

Room temperature in continental US; may vary elsewhere.

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.

• [1]. Sheila M, et al. CEP-40783: A potent and selective AXL/c-Met inhibitor for use in breast, non-small cell lung (NSCLC), and pancreatic cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C275.

  [2]. Jay F, et al. Antitumor activity of the dual AXL/c-Met inhibitor CEP-40783 in Champions primary TumorGraft? models of human non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C272.