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SAR of Carbon‐Linked, 2‐Substituted Purines: Synthesis and Characterization of AP23451 as a novel Bone‐Targeted Inhibitor of Src Tyrosine Kinase With In Vivo Anti‐Resorptive Activity
Author(s) -
Shakespeare William C.,
Wang Yihan,
Bohacek Regine,
Keenan Terry,
Sundaramoorthi Raji,
Metcalf Chet,
Dilauro Anne,
Roeloffzen Sonya,
Liu Shuangying,
Saltmarsh Jennifer,
Paramanathan Guru,
Dalgarno David,
Narula Surinder,
Pradeepan Selvi,
Van Schravendijk Marie Rose,
Keats Jeff,
Ram Mary,
Liou Shuenn,
Adams Susan,
Wardwell Scott,
Bogus Julie,
Iuliucci John,
Weigele Manfred,
Xing Lianping,
Boyce Brendan,
Sawyer Tomi K.
Publication year - 2008
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2007.00615.x
Subject(s) - proto oncogene tyrosine protein kinase src , in vivo , bone resorption , tyrosine kinase , chemistry , tyrosine protein kinase csk , osteoclast , biochemistry , tyrosine , kinase , microbiology and biotechnology , sh3 domain , in vitro , signal transduction , biology , endocrinology
Targeted disruption of the pp60 src (Src) gene has implicated this tyrosine kinase in osteoclast‐mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone‐related diseases. Here, we describe structure activity relationships of a novel series of carbon‐linked, 2‐substituted purines that led to the identification of AP23451 as a potent inhibitor of Src tyrosine kinase with antiresorptive activity in vivo . AP23451 features the use of an arylphosphinylmethylphosphinic acid moiety which confers bone‐targeting properties to the molecule, thereby increasing local concentrations of the inhibitor to actively resorbing osteoclasts at the bone interface. AP23451 exhibited an IC 50 = 68 n m against Src kinase; an X‐ray crystal structure of the molecule complexed with Src detailed the molecular interactions responsible for its Src inhibition. In vivo , AP23451 demonstrated a dose‐dependent decrease in PTH‐induced hypercalcemia. Moreover, AP23517, a structurally and biochemically similar molecule with comparable activity (IC 50 = 73 n m ) except devoid of the bone‐targeting element, demonstrated significantly reduced in vivo efficacy, suggesting that Src activity was necessary but not sufficient for in vivo activity in this series of compounds.