title: The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer.
abstract: The heterogeneity and severity of certain autoimmune diseases and B-cell malignancies warrant simultaneous targeting of multiple disease-relevant signaling pathways. Dual inhibition of spleen tyrosine kinase (SYK) and Janus kinase (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. To this end, we provide data on the discovery and preclinical development of PRT062070 [4-(cyclopropylamino)-2-({4-[4-(ethylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidine-5-carboxamide hydrochloride], an orally active kinase inhibitor that demonstrates activity against SYK and JAK. Cellular assays demonstrated specific inhibitory activity against signaling pathways that use SYK and JAK1/3. Limited inhibition of JAK2 was observed, and PRT062070 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, PRT062070 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. PRT062070 is currently under evaluation in a phase I dose escalation study in patients with B-cell leukemia and lymphoma (NCT01994382), with proof-of-concept studies in humans planned to assess therapeutic potential in autoimmune and malignant diseases.
authors.affiliation: Portola Pharmaceuticals, Inc., San Francisco, California gcoffey@portola.com.
authors.forename: Greg
authors.initials: G
authors.lastname: Coffey
authors.affiliation: Portola Pharmaceuticals, Inc., San Francisco, California.
authors.forename: Andreas
authors.initials: A
authors.lastname: Betz
authors.affiliation: Portola Pharmaceuticals, Inc., San Francisco, California.
authors.forename: Francis
authors.initials: F
authors.lastname: DeGuzman
authors.affiliation: Portola Pharmaceuticals, Inc., San Francisco, California.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Pak
authors.affiliation: Portola Pharmaceuticals, Inc., San Francisco, California.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Inagaki
authors.affiliation: Portola Pharmaceuticals, Inc., San Francisco, California.
authors.forename: Dale C
authors.initials: DC
authors.lastname: Baker
authors.affiliation: Portola Pharmaceuticals, Inc., San Francisco, California.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Hollenbach
authors.affiliation: Portola Pharmaceuticals, Inc., San Francisco, California.
authors.forename: Anjali
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Portola Pharmaceuticals, Inc., San Francisco, California.
authors.forename: Uma
authors.initials: U
authors.lastname: Sinha
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity / Q000187:drug effects* / Q000502:physiology; D002417:Cattle; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: C000595259:4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013450:Sulfones