title: Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.
abstract: In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Wei-Sheng
authors.initials: WS
authors.lastname: Huang
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Shuangying
authors.initials: S
authors.lastname: Liu
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Dong
authors.initials: D
authors.lastname: Zou
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Mathew
authors.initials: M
authors.lastname: Thomas
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Tianjun
authors.initials: T
authors.lastname: Zhou
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Jan
authors.initials: J
authors.lastname: Romero
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Kohlmann
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Qi
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Lisi
authors.initials: L
authors.lastname: Cai
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Dwight
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Rongsong
authors.initials: R
authors.lastname: Xu
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Rory
authors.initials: R
authors.lastname: Dodd
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Angela
authors.initials: A
authors.lastname: Toms
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Lois
authors.initials: L
authors.lastname: Parillon
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Lu
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Rana
authors.initials: R
authors.lastname: Anjum
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Sen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Wang
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Keats
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Wardwell
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Yaoyu
authors.initials: Y
authors.lastname: Ning
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Qihong
authors.initials: Q
authors.lastname: Xu
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Moran
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Qurish K
authors.initials: QK
authors.lastname: Mohemmad
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Hyun Gyung
authors.initials: HG
authors.lastname: Jang
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Tim
authors.initials: T
authors.lastname: Clackson
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Narayana I
authors.initials: NI
authors.lastname: Narasimhan
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Rivera
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhu
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: David
authors.initials: D
authors.lastname: Dalgarno
authors.affiliation: ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: William C
authors.initials: WC
authors.lastname: Shakespeare
mesh_terms: D000284:Administration, Oral; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008968:Molecular Conformation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010720:Phosphines / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D010720:Phosphines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C044646:phosphine; C000598580:brigatinib