Cerdulatinib HCl(cas# 1369761-01-2), also known as PRT-062070 or PRT2070, is an novel oral dual Syk/JAK inhibitor. Cerdulatinib is currently being studied in patients with genetically-defined hematologic cancers, as well as for patients who have failed therapy due to relapse or acquired mutations.
As a dual SYK/JAK inhibitor, Cerdulatinib significantly reduces cell viability in a subset of NHL cell lines, and induces apoptosis in BCR-signaling competent NHL cell lines.
1. Clin Cancer Res. 2017 May 1;23(9):2313-2324. doi: 10.1158/1078-0432.CCR-16-1662.
Epub 2016 Oct 3.
The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and
Microenvironmental Signaling in Chronic Lymphocytic Leukemia.
Blunt MD(1), Koehrer S(2), Dobson RC(1), Larrayoz M(1), Wilmore S(1), Hayman
A(1), Parnell J(1), Smith LD(1), Davies A(1), Johnson PWM(1), Conley PB(3),
Pandey A(3), Strefford JC(1), Stevenson FK(1), Packham G(1), Forconi F(1)(4),
Coffey GP(3), Burger JA(2), Steele AJ(5).
(1)Cancer Sciences Unit (MP824), University of Southampton, Southampton, United
(2)Department of Leukemia, Division of Cancer Medicine, The University of Texas
MD Anderson Cancer Center, Houston, Texas.
(3)Portola Pharmaceuticals, South San Francisco, California.
(4)Haematology Department at the University Hospital Southampton NHS Trust,
Southampton, United Kingdom.
(5)Cancer Sciences Unit (MP824), University of Southampton, Southampton, United
Purpose: B-cell receptor (BCR)-associated kinase inhibitors, such as ibrutinib,
have revolutionized the treatment of chronic lymphocytic leukemia (CLL). However,
these agents are not curative, and resistance is already emerging in a proportion
of patients. IL4, expressed in CLL lymph nodes, can augment BCR signaling and
reduce the effectiveness of BCR kinase inhibitors. Therefore, simultaneous
targeting of the IL4- and BCR signaling pathways by cerdulatinib, a novel dual
Syk/JAK inhibitor currently in clinical trials (NCT01994382), may improve
treatment responses in patients.Experimental Design: PBMCs from patients with CLL
were treated in vitro with cerdulatinib alone or in combination with venetoclax.
Cell death, chemokine, and cell signaling assay were performed and analyzed by
flow cytometry, immunoblotting, q-PCR, and ELISA as indicated.Results: At
concentrations achievable in patients, cerdulatinib inhibited BCR- and
IL4-induced downstream signaling in CLL cells using multiple readouts and
prevented anti-IgM- and nurse-like cell (NLC)-mediated CCL3/CCL4 production.
Cerdulatinib induced apoptosis of CLL cells, in a time- and
concentration-dependent manner, and particularly in IGHV-unmutated samples with
greater BCR signaling capacity and response to IL4, or samples expressing higher
levels of sIgM, CD49d+, or ZAP70+ Cerdulatinib overcame anti-IgM, IL4/CD40L, or
NLC-mediated protection by preventing upregulation of MCL-1 and BCL-XL; however,
BCL-2 expression was unaffected. Furthermore, in samples treated with IL4/CD40L,
cerdulatinib synergized with venetoclax in vitro to induce greater apoptosis than
either drug alone.Conclusions: Cerdulatinib is a promising therapeutic for the
treatment of CLL either alone or in combination with venetoclax, with the
potential to target critical survival pathways in this currently incurable
disease. Clin Cancer Res; 23(9); 2313-24. ©2016 AACR.
2. Oncotarget. 2017 Feb 21;8(8):12953-12967. doi: 10.18632/oncotarget.14588.
Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic
leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells
protected by the microenvironment.
Guo A(1), Lu P(1), Coffey G(2), Conley P(2), Pandey A(2), Wang YL(1).
(1)Department of Pathology, Lymphoma Translational Pathology, University of
Chicago, Chicago, IL, USA.
(2)Portola Pharmaceuticals, Inc., South San Francisco, CA, USA.
Ibrutinib (BTK inhibitor) has generated remarkable responses in CLL. However, the
drug, to a large extent, does not cause cell death directly and does not
eradicate CLL malignant clones. Inability to eradicate CLL has fostered
resistance generation. Once patients become resistant, they do poorly with a
median survival of 3-4 months. Novel therapeutic strategies are needed to prevent
resistance, improve treatment outcome and ultimately cure the disease. Herein, we
explore dual targeting of the BCR and JAK-STAT pathways with a novel single
agent, cerdulatinib, which selectively inhibits both SYK (a BCR component) and
JAK kinases. We demonstrated that cerdulatinib delivered potent tumor inhibition
in 60 primary CLL patient samples, especially in those with poor prognostic
indicators. Importantly, cerdulatinib, but not ibrutinib, is able to overcome the
support of microenvironment and induces CLL cell death at clinically achievable
concentrations. Notably, cerdulatinib blocked proliferation of
ibrutinib-resistant primary CLL cells and of
BTKC481S-transfected/ibrutinib-resistant lymphoma cells. These anti-tumor effects
are well correlated with the inhibition of BCR and JAK-STAT signaling and
downstream inhibition of the functions of AKT, ERK and NFκB. Collectively, our
results show that simultaneous targeting of BCR and JAK-STAT pathways is a more
effective strategy relative to single BTK inhibition.