Wednesday, August 5, 2015

Drugs in Clinical Pipeline: Cerdulatinib

Cerdulatinib [4-(cyclopropylamino)-2-({4-[4-(ethylsulfonyl)piperazin-1-yl]phenyl}amino) pyrimidine-5-carboxamide], is an orally active kinase inhibitor that demonstrates activity against spleen tyrosine kinase (SYK, IC50 = 32 nM) and Janus kinase (JAK1, 2, 3 IC50 = 12, 6, 8 nM, respectively) [1].

Dual inhibition of SYK and JAK represents such a strategy and may elicit several benefits relative to selective kinase inhibition, such as gaining control over a broader array of disease etiologies, reducing probability of selection for bypass disease mechanisms, and the potential that an overall lower level suppression of individual targets may be sufficient to modulate disease activity.

Cerdulatinib behaves like a multikinase inhibitor as in specificity assays it showed affinity towards other kinases also. It inhibited nearly 25 tested kinases with IC50 less than 200 nM. Cerdulatinib blocks the B-cell receptor pathway via Syk and cytokine pathways via JAK 1, 3 and Tyk 2, hence it has a unique profile where it inhibits two validated tumor proliferation pathways that contribute to tumor cell growth and survival in certain hematologic malignancies. Moreover, Cerdulatinib has a favorable pharmacokinetic profile with a half-life of 14-18 hours that supports once-daily dosing. There parameters suggest that Cerdulatinib can be used in treatment of patients with genetically-defined hematologic cancers, as well as those who have failed therapy due to relapse or acquired mutations.

Cerdulatinib was discovered at Portola Pharmaceuticals. A Phase 1/2a study involving Cerdulatinib is ongoing in chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (NHL) patients. Results of in vitro studies suggest that the anti-tumor activity of Cerdulatinib is mediated by dual inhibition of Syk and JAK signaling pathways, and that Cerdulatinib may be a potent treatment for diffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin’s lymphoma (NHL). Cerdulatinib also has shown in vitro efficacy in ibrutinib-resistant chronic lymphocytic leukemia (CLL) and in DLBCL with certain mutations.

The activity of Cerdulatinib is as follows:

IC50 (SYK enzyme assay) = 32 nM
IC50 (JAK1 enzyme assay) = 12 nM
IC50 (JAK2 enzyme assay) = 6 nM
IC50 (JAK3 enzyme assay) = 8 nM
IC50 (TYK2 enyme assay) =  0.5  nM
IC50 (MST1 enyme assay) = 4  nM
IC50 (ARK5 enyme assay) = 4  nM
IC50 (MLK1 enyme assay) = 5  nM
IC50 (Fms enyme assay) = 5  nM
IC50 (AMPK enyme assay) = 6  nM
IC50 (TBK1 enyme assay) = 10  nM
IC50 (MARK1 enyme assay) = 10  nM
IC50 (PAR1B-a enyme assay) = 13  nM
IC50 (TSSK enyme assay) = 14  nM
IC50 (MST2 enyme assay) = 15  nM
IC50 (GCK enyme assay) = 18  nM
IC50 (JNK3 enyme assay) = 18  nM
IC50 (RSK2 enyme assay) = 20  nM
IC50 (RSK4 enyme assay) = 28  nM
IC50 (Chk1 enyme assay) = 42  nM
IC50 (FLT4 enyme assay) = 51  nM
IC50 (FLT3 enyme assay) = 90  nM
IC50 (RET enyme assay) = 105  nM
IC50 (ITK enyme assay) = 194  nM

Common Name: Cerdulatinib
Synonyms:  PRT2070; PRT-2070; PRT 2070; PRT-062070; PRT 062070; PRT062070
IUPAC Name: 4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino) pyrimidine-5-carboxamide
CAS Number: 1198300-79-6
Mechanism of Action: Kinase Inhibitor; Dual-Kinase Inhibitor; SYK Inhibitor; JAK Inhibitor
Indication: Various Cancers; Chronic Lymphocytic Leukemia; B-cell Non-Hodgkin Lymphoma
Development Stage: Phase II
Company: Portola Pharmaceuticals

In cellular assays Cerdulatinib demonstrated specific inhibitory activity against signaling pathways that use SYK and JAK1/3. Limited inhibition of JAK2 was observed, and Cerdulatinib did not inhibit phorbol 12-myristate 13-acetate-mediated signaling or activation in B and T cells nor T-cell antigen receptor-mediated signaling in T cells, providing evidence for selectivity of action. Potent antitumor activity was observed in a subset of B-cell lymphoma cell lines. After oral dosing, Cerdulatinib suppressed inflammation and autoantibody generation in a rat collagen-induced arthritis model and blocked B-cell activation and splenomegaly in a mouse model of chronic B-cell antigen receptor stimulation [1].      

1. Coffey, G.; et. al. The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther 2014, 351(3), 538-548.