| Reference | 1. J Med Chem. 2016 Aug 25;59(16):7478-96. doi: 10.1021/acs.jmedchem.6b00487. Epub
2016 Aug 15.
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Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal
Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK).
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Ott GR(1), Cheng M(1), Learn KS(1), Wagner J(1), Gingrich DE(1), Lisko JG(1),
Curry M(1), Mesaros EF(1), Ghose AK(1), Quail MR(1), Wan W(1), Lu L(1),
Dobrzanski P(1), Albom MS(1), Angeles TS(1), Wells-Knecht K(1), Huang Z(1),
Aimone LD(1), Bruckheimer E(2), Anderson N(2), Friedman J(2), Fernandez SV(3),
Ator MA(1), Ruggeri BA(1), Dorsey BD(1).
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Author information: <br>
(1)Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West
Chester, Pennsylvania 19380, United States.
(2)Champions Oncology, Inc. , One University Plaza, Suite 307, Hackensack, New
Jersey 07601, United States.
(3)Thomas Jefferson University , 233 South 10th Street, 1002 BLSB, Philadelphia,
Pennsylvania 19107, United States.
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Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1
were optimized for metabolic stability. The results from this endeavor not only
led to improved metabolic stability, pharmacokinetic parameters, and in vitro
activity against clinically derived resistance mutations but also led to the
incorporation of activity for focal adhesion kinase (FAK). FAK activation, via
amplification and/or overexpression, is characteristic of multiple invasive solid
tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK
inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology,
and pharmacokinetics, is reported herein.
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2. Breast Cancer Res. 2016 Mar 24;18(1):37. doi: 10.1186/s13058-016-0694-4.
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The effects of CEP-37440, an inhibitor of focal adhesion kinase, in vitro and in
vivo on inflammatory breast cancer cells.
<br><br>
Salem I(1), Alsalahi M(1), Chervoneva I(2), Aburto LD(1), Addya S(3), Ott GR(4),
Ruggeri BA(4)(5), Cristofanilli M(1)(6), Fernandez SV(7).
<br>
Author information: <br>
(1)Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA,
USA.
(2)Division of Biostatistics, Department of Pharmacology and Experimental
Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
(3)Cancer Genomics Facility, Kimmel Cancer Center, Thomas Jefferson University,
Philadelphia, PA, USA.
(4)Teva Branded Pharmaceutical Products R&D, West Chester, PA, USA.
(5)Present address: Incyte Pharmaceuticals, Wilmington, DE, USA.
(6)Present address: Department of Medicine – Hematology and Oncology, Robert H.
Curie, Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
(7)Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA,
USA. [email protected].
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BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive type of advanced
breast cancer with a poor prognosis. We recently found that focal adhesion kinase
1 (FAK1) is upregulated and phosphorylated (active) in IBC. In this study, we
investigated the effect of CEP-37440, a dual inhibitor of FAK1 and anaplastic
lymphoma kinase (ALK), using human IBC cell lines and preclinical models of IBC.
METHODS: Cell proliferation assays were performed in the presence of several
concentrations of CEP-37440 using IBC and triple-negative breast cancer non-IBC
cell lines. In vitro, we studied the expression of total FAK1, phospho-FAK1 (Tyr
397), total ALK and phospho-ALK (Tyr 1604). In vivo, we tested CEP-37440 using
FC-IBC02, SUM149, and SUM190 IBC xenograft mouse models.<br>
RESULTS: CEP-37440 at low concentration decreased the proliferation of the IBC
cell lines FC-IBC02, SUM190, and KPL4, while not affecting the proliferation of
normal breast epithelial cells. At higher concentration, CEP-37440 was also able
to inhibit the proliferation of the IBC cell line MDA-IBC03 and the
triple-negative non-IBC cell lines MDA-MB-231 and MDA-MB-468; the IBC cell line
SUM149 showed a slight response to the drug. CEP-37440 decreased the cell
proliferation of FC-IBC02, SUM190, and KPL4 by blocking the autophosphorylation
kinase activity of FAK1 (Tyr 397). None of the cells evaluated expressed ALK. In
vivo, after 7 weeks of CEP-37440 treatment, the SUM190, FC-IBC02, and SUM149
breast tumor xenografts were smaller in mice treated with 55 mg/kg bid CEP-37440
compared to the controls; the tumor growth inhibition (TGI) was 79.7 %, 33 %, and
23 %, respectively. None of the FC-IBC02 breast xenografts mice treated with
CEP-37440 developed brain metastasis while 20 % of the mice in the control group
developed brain metastasis. Expression array analyses in FC-IBC02 cells showed
that CEP-37440 affects the expression of genes related to apoptosis, interferon
signaling, and cytokines.<br>
CONCLUSIONS: CEP-37440 is effective against some IBC cells that express
phospho-FAK1 (Tyr 397), and its antiproliferative activity is related to its
ability to decrease phospho-FAK1. Our results suggest that combinational
therapies could be more effective than using CEP-37440 as a single agent.
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