title: The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia.
abstract: Purpose:Acalabrutinib (ACP-196) is a novel, potent, and highly selective Bruton tyrosine kinase (BTK) inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the antitumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL).Experimental Design:Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model. Mice received either vehicle or acalabrutinib formulated into the drinking water.Results:Utilizing biochemical assays, we demonstrate that acalabrutinib is a highly selective BTK inhibitor as compared with ibrutinib. In the human CLL NSG xenograft model, treatment with acalabrutinib demonstrated on-target effects, including decreased phosphorylation of PLCγ2, ERK, and significant inhibition of CLL cell proliferation. Furthermore, tumor burden in the spleen of the mice treated with acalabrutinib was significantly decreased compared with vehicle-treated mice. Similarly, in the TCL1 adoptive transfer model, decreased phosphorylation of BTK, PLCγ2, and S6 was observed. Most notably, treatment with acalabrutinib resulted in a significant increase in survival compared with mice receiving vehicle.Conclusions:Treatment with acalabrutinib potently inhibits BTKin vivo, leading to on-target decreases in the activation of key signaling molecules (including BTK, PLCγ2, S6, and ERK). In two complementary mouse models of CLL, acalabrutinib significantly reduced tumor burden and increased survival compared with vehicle treatment. Overall, acalabrutinib showed increased BTK selectivity compared with ibrutinib while demonstrating significant antitumor efficacyin vivoon par with ibrutinib.Clin Cancer Res; 23(11); 2831-41. ©2016 AACR.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Sarah E M
authors.initials: SEM
authors.lastname: Herman
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.|Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Montraveta
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.|Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Carsten U
authors.initials: CU
authors.lastname: Niemann
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Helena
authors.initials: H
authors.lastname: Mora-Jensen
authors.affiliation: Acerta Pharma, Redwood City, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Gulrajani
authors.affiliation: Acerta Pharma, Redwood City, California.
authors.forename: Fanny
authors.initials: F
authors.lastname: Krantz
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Rose
authors.initials: R
authors.lastname: Mantel
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Smith
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Fabienne
authors.initials: F
authors.lastname: McClanahan
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Bonnie K
authors.initials: BK
authors.lastname: Harrington
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.affiliation: Acerta Pharma, Redwood City, California.
authors.forename: Todd
authors.initials: T
authors.lastname: Covey
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Acerta Pharma, Redwood City, California.
authors.forename: Raquel
authors.initials: R
authors.lastname: Izumi
authors.affiliation: Acerta Pharma, Redwood City, California.
authors.forename: Allard
authors.initials: A
authors.lastname: Kaptein
authors.affiliation: Acerta Pharma, Redwood City, California.
authors.forename: Roger
authors.initials: R
authors.lastname: Ulrich
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Acerta Pharma, Redwood City, California.|Oncternal Therapeutics, San Diego, California.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lannutti
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland. jennifer.woyach@osumc.edu wiestnea@mail.nih.gov.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio. jennifer.woyach@osumc.edu wiestnea@mail.nih.gov.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D019264:Adoptive Transfer / Q000379:methods; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage*; D004195:Disease Models, Animal; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011719:Pyrazines / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011719:Pyrazines; D011720:Pyrazoles; D011743:Pyrimidines; C490393:Tcl1 protein, mouse; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C000604908:acalabrutinib; D000225:Adenine