title: Anti-leukaemic activity of the TYK2 selective inhibitor NDI-031301 in T-cell acute lymphoblastic leukaemia.
abstract: Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukaemia (T-ALL) cells. Here we demonstrate the anti-leukaemic activity of a novel TYK2 inhibitor, NDI-031301. NDI-031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T-ALL cell lines. NDI-031301 treatment of human T-ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI-031301 treatment uniquely leads to activation of three mitogen-activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage. Activation of p38 MAPK occurred within 1 h of NDI-031301 treatment and was responsible for NDI-031301-induced T-ALL cell death, as pharmacological inhibition of p38 MAPK partially rescued apoptosis induced by TYK2 inhibitor. Finally, daily oral administration of NDI-031301 at 100 mg/kg bid to immunodeficient mice engrafted with KOPT-K1 T-ALL cells was well tolerated, and led to decreased tumour burden and a significant survival benefit. These results support selective inhibition of TYK2 as a promising potential therapeutic strategy for T-ALL.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Akahane
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Zhaodong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Etchin
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Alla
authors.initials: A
authors.lastname: Berezovskaya
authors.affiliation: Center for Immuno - Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Evisa
authors.initials: E
authors.lastname: Gjini
authors.affiliation: Nimbus Therapeutics, Cambridge, MA, USA.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Masse
authors.affiliation: Nimbus Therapeutics, Cambridge, MA, USA.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Miao
authors.affiliation: Nimbus Therapeutics, Cambridge, MA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rocnik
authors.affiliation: Nimbus Therapeutics, Cambridge, MA, USA.
authors.forename: Rosana
authors.initials: R
authors.lastname: Kapeller
authors.affiliation: Schrödinger, Inc., New York, NY, USA.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Greenwood
authors.affiliation: Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Tiv
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Sanda
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D053634:TYK2 Kinase; C070139:TYK2 protein, human
keywords: NDI-031301; T-cell acute lymphoblastic leukaemia; TYK2; p38 MAPK