BACKGROUND: The secosteroid 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) acts through the vitamin D receptor (VDR) to elicit many activities that make it a promising drug candidate for the treatment of a number of diseases, including cancer and psoriasis. Clinical use of 1,25(OH)2D3 has been limited by hypercalcemia elicited by pharmacologically effective doses. We hypothesized that structurally distinct, nonsecosteroidal mimics of 1,25(OH)2D3 might have different activity profiles from vitamin D analogs, and set out to discover such compounds by screening small-molecule libraries. RESULTS: A bis-phenyl derivative was found to activate VDR in a transactivation screening assay. Additional related compounds were synthesized that mimicked various activities of 1,25(OH)2D3, including growth inhibition of cancer cells and keratinocytes, as well as induction of leukemic cell differentiation. In contrast to 1, 25(OH)2D3, these synthetic compounds did not demonstrate appreciable binding to serum vitamin D binding protein, a property that is correlated with fewer calcium effects in vivo. Two mimics tested in mice showed greater induction of a VDR target gene with less elevation of serum calcium than 1,25(OH)2D3. CONCLUSIONS: These novel VDR modulators may have potential as therapeutics for cancer, leukemia and psoriasis with less calcium mobilization side effects than are associated with secosteroidal 1,25(OH)2D3 analogs.
BACKGROUND: The secosteroid 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) acts through the vitamin D receptor (VDR) to elicit many activities that make it a promising drug candidate for the treatment of a number of diseases, including cancer and psoriasis. Clinical use of 1,25(OH)2D3 has been limited by hypercalcemia elicited by pharmacologically effective doses. We hypothesized that structurally distinct, nonsecosteroidal mimics of 1,25(OH)2D3 might have different activity profiles from vitamin D analogs, and set out to discover such compounds by screening small-molecule libraries. RESULTS: A bis-phenyl derivative was found to activate VDR in a transactivation screening assay. Additional related compounds were synthesized that mimicked various activities of 1,25(OH)2D3, including growth inhibition of cancer cells and keratinocytes, as well as induction of leukemic cell differentiation. In contrast to 1, 25(OH)2D3, these synthetic compounds did not demonstrate appreciable binding to serum vitamin D binding protein, a property that is correlated with fewer calcium effects in vivo. Two mimics tested in mice showed greater induction of a VDR target gene with less elevation of serum calcium than 1,25(OH)2D3. CONCLUSIONS: These novel VDR modulators may have potential as therapeutics for cancer, leukemia and psoriasis with less calcium mobilization side effects than are associated with secosteroidal 1,25(OH)2D3 analogs.
Authors: Kelly Teske; Premchendar Nandhikonda; Jonathan W Bogart; Belaynesh Feleke; Preetpal Sidhu; Nina Yuan; Joshua Preston; Robin Goy; Lanlan Han; Nicholas R Silvaggi; Rakesh K Singh; Daniel D Bikle; James M Cook; Leggy A Arnold Journal: Nucl Receptor Res Date: 2014
Authors: Kelly Teske; Premchendar Nandhikonda; Jonathan W Bogart; Belaynesh Feleke; Preetpal Sidhu; Nina Yuan; Joshua Preston; Robin Goy; Leggy A Arnold Journal: J Biomol Res Ther Date: 2014
Authors: Arnaud Teichert; Leggy A Arnold; Steve Otieno; Yuko Oda; Indre Augustinaite; Tim R Geistlinger; Richard W Kriwacki; R Kiplin Guy; Daniel D Bikle Journal: Biochemistry Date: 2009-02-24 Impact factor: 3.162
Authors: Yanfei Ma; Berket Khalifa; Ying K Yee; Jianfen Lu; Ai Memezawa; Rajesh S Savkur; Yoko Yamamoto; Subba R Chintalacharuvu; Kazuyoshi Yamaoka; Keith R Stayrook; Kelli S Bramlett; Qing Q Zeng; Srinivasan Chandrasekhar; Xiao-Peng Yu; Jared H Linebarger; Stephen J Iturria; Thomas P Burris; Shigeaki Kato; William W Chin; Sunil Nagpal Journal: J Clin Invest Date: 2006-03-09 Impact factor: 14.808
Authors: Premchendar Nandhikonda; Wen Z Lynt; Megan M McCallum; Tahniyath Ara; Athena M Baranowski; Nina Y Yuan; Dana Pearson; Daniel D Bikle; R Kiplin Guy; Leggy A Arnold Journal: J Med Chem Date: 2012-05-16 Impact factor: 7.446