title: Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant.
abstract: Ponatinib (AP24534) was previously identified as a pan-BCR-ABL inhibitor that potently inhibits the T315I gatekeeper mutant, and has advanced into clinical development for the treatment of refractory or resistant CML. In this study, we explored a novel series of five and six membered monocycles as alternate hinge-binding templates to replace the 6,5-fused imidazopyridazine core of ponatinib. Like ponatinib, these monocycles are tethered to pendant toluanilides via an ethynyl linker. Several compounds in this series displayed excellent in vitro potency against both native BCR-ABL and the T315I mutant. Notably, a subset of inhibitors exhibited desirable PK and were orally active in a mouse model of T315I-driven CML.
authors.affiliation: ARIAD Pharmaceuticals Inc., 26 Lansdowne Street, Cambridge, MA 02139, USA. Mathew.thomas@ariad.com
authors.forename: Mathew
authors.initials: M
authors.lastname: Thomas
authors.forename: Wei-Sheng
authors.initials: WS
authors.lastname: Huang
authors.forename: David
authors.initials: D
authors.lastname: Wen
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhu
authors.forename: Yihan
authors.initials: Y
authors.lastname: Wang
authors.forename: Chester A
authors.initials: CA
authors.lastname: Metcalf
authors.forename: Shuangying
authors.initials: S
authors.lastname: Liu
authors.forename: Ingrid
authors.initials: I
authors.lastname: Chen
authors.forename: Jan
authors.initials: J
authors.lastname: Romero
authors.forename: Dong
authors.initials: D
authors.lastname: Zou
authors.forename: Raji
authors.initials: R
authors.lastname: Sundaramoorthi
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Jiwei
authors.initials: J
authors.lastname: Qi
authors.forename: Lisi
authors.initials: L
authors.lastname: Cai
authors.forename: Tianjun
authors.initials: T
authors.lastname: Zhou
authors.forename: Lois
authors.initials: L
authors.lastname: Commodore
authors.forename: Qihong
authors.initials: Q
authors.lastname: Xu
authors.forename: Jeff
authors.initials: J
authors.lastname: Keats
authors.forename: Frank
authors.initials: F
authors.lastname: Wang
authors.forename: Scott
authors.initials: S
authors.lastname: Wardwell
authors.forename: Yaoyu
authors.initials: Y
authors.lastname: Ning
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Snodgrass
authors.forename: Marc I
authors.initials: MI
authors.lastname: Broudy
authors.forename: Karin
authors.initials: K
authors.lastname: Russian
authors.forename: John
authors.initials: J
authors.lastname: Iuliucci
authors.forename: Victor M
authors.initials: VM
authors.lastname: Rivera
authors.forename: Tomi K
authors.initials: TK
authors.lastname: Sawyer
authors.forename: David C
authors.initials: DC
authors.lastname: Dalgarno
authors.forename: Tim
authors.initials: T
authors.lastname: Clackson
authors.forename: William C
authors.initials: WC
authors.lastname: Shakespeare
mesh_terms: D000284:Administration, Oral; D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D003500:Cyclization; D004195:Disease Models, Animal; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D051381:Rats; D013329:Structure-Activity Relationship; D014050:Toluene / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000480:Alkynes; D000814:Aniline Compounds; D014050:Toluene; D016044:Fusion Proteins, bcr-abl; C023650:aniline