Discovery of an Orally Efficacious Inhibitor of Anaplastic Lymphoma Kinase

Abstract

Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancer, supported by considerable favorable preclinical and clinical activities over the past several years and culminating in the recent FDA approval of the ALK inhibitor crizotinib. Through a series of targeted modifications on an ALK inhibitor diaminopyrimidine scaffold, our research group has driven improvements in ALK potency, kinase selectivity, and overall pharmaceutical properties. Optimization of this scaffold has led to the identification of a potent and efficacious inhibitor of ALK, 25b. A striking feature of 25b over previously described ALK inhibitors is its >600-fold selectivity over insulin receptor (IR), a closely related kinase family member. Most importantly, 25b exhibited dose proportional escalation in rat compared to compound 3 which suffered dose limiting absorption preventing further advancement. Compound 25b exhibited significant in vivo antitumor efficacy when dosed orally in an ALK-positive ALCL tumor xenograft model in SCID mice, warranting further assessment in advanced preclinical models.

Preparation of Tetrabenzo[4.4.2]undecastarphene by On‐Surface Synthesis

“…The preparation starts from 1,2-bis(bromomethyl)-4-methoxybenzene 4 which can be obtained from dimethyl 4-methoxy-1,2-benzenedicarboxylate by reduction of the two ester functions followed by bromination of the two alcohol groups by PBr3 in dichloromethane. [18], [19] Metallation of 4 by ethylmagnesium bromide followed by copper coupling with trilmethylsilyl acetylene gave 5. Deprotection by tetrabutylammonium fluoride in THF yielded 6.…”

Synthesis and pharmacological evaluation of fluorinated benzo[7]annulen‐7‐amines as GluN2B‐selective NMDA receptor antagonists

“…Ketones 5a and 5b bearing a Br‐atom and OCH 3 group in 2‐position were selected as key intermediates for the synthesis of benzo[7]annulen‐7‐amines. 2‐Bromo‐5,6,8,9‐tetrahydrobenzo[7]annulen‐7‐one ( 5a ) was obtained in five reaction steps from phthalic anhydride ( 7 ), whereas the five step synthesis of ketone 5b with a OCH 3 moiety in 2‐position started from 3,4‐dimethylanisol ( 8 ) . Demethylation of methyl ether 5b with HBr led to phenol 5d , which was converted into fluoroethoxy derivative 5f by alkylation with (2‐fluoroethyl) tosylate.…”

NK/T-cell lymphomas in children

“…In terms of novel agents for ALCL, brentuximab vedotin – an antibody-drug conjugate directed against CD30 – has been used successfully in adults with relapsed ALCL but has not been tested in children 56–58 . The ALK inhibitor – crizotinib – has also shown promise in early trials 59,60 .…”