GSK-3 inhibition by an orally active small molecule increases bone mass in rats

Bone ◽  
2012 ◽  
Vol 50 (3) ◽  
pp. 619-627 ◽  
Author(s):  
Richard Marsell ◽  
Gregor Sisask ◽  
Yvonne Nilsson ◽  
Anna K. Sundgren-Andersson ◽  
Ulf Andersson ◽  
...  
Keyword(s):  
Bone Mass ◽  
Small Molecule ◽  
Orally Active

P2-481: Small molecule BACE-1 inhibitors are potent, selective and orally active

2008 ◽  
Vol 4 ◽  
pp. T515-T515
Author(s):  
Michael Malamas ◽  
Jim Erdei ◽  
Iwan Gunawan ◽  
Albert Robichaud ◽  
Jim Turner ◽  
...  
Keyword(s):  
Small Molecule ◽  
Orally Active ◽  
Bace 1

scholarly journals Synthesis and evaluation of orally active small molecule HIV-1 Nef antagonists

2016 ◽  
Vol 26 (5) ◽  
pp. 1480-1484 ◽  
Author(s):  
Lori A. Emert-Sedlak ◽  
H. Marie Loughran ◽  
Haibin Shi ◽  
John L. Kulp ◽  
Sherry T. Shu ◽  
...  
Keyword(s):  
Small Molecule ◽  
Orally Active ◽  
Hiv 1

scholarly journals Discovery of a Novel Orally Active Small-Molecule gp130 Inhibitor for the Treatment of Ovarian Cancer

2013 ◽  
Vol 12 (6) ◽  
pp. 937-949 ◽  
Author(s):  
Shili Xu ◽  
Fedora Grande ◽  
Antonio Garofalo ◽  
Nouri Neamati
Keyword(s):  
Ovarian Cancer ◽  
Small Molecule ◽  
Orally Active

scholarly journals Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase

2007 ◽  
Vol 104 (10) ◽  
pp. 4106-4111 ◽  
Author(s):  
M. G. Manfredi ◽  
J. A. Ecsedy ◽  
K. A. Meetze ◽  
S. K. Balani ◽  
O. Burenkova ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Molecule Inhibitor ◽  
Orally Active

Discovery of a Novel, Orally Active, Small Molecule Gonadotropin-Releasing Hormone (GnRH) Receptor Antagonist

2006 ◽  
Vol 49 (11) ◽  
pp. 3362-3367 ◽  
Author(s):  
Haitao Li ◽  
Kenna L. Anderes ◽  
Eugenia A. Kraynov ◽  
David R. Luthin ◽  
Quyen-Quyen Do ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Small Molecule ◽  
Gnrh Receptor ◽  
Gonadotropin Releasing Hormone ◽  
Releasing Hormone ◽  
Orally Active

scholarly journals A small molecule compound berberine as an orally active therapeutic candidate against COVID‐19 and SARS: A computational and mechanistic study

2021 ◽  
Vol 35 (4) ◽  
Author(s):  
Zhen‐Zhen Wang ◽  
Kun Li ◽  
Anish R. Maskey ◽  
Weihua Huang ◽  
Anton A. Toutov ◽  
...  
Keyword(s):  
Small Molecule ◽  
Mechanistic Study ◽  
Small Molecule Compound ◽  
Orally Active

A novel, selective, orally active, potent small molecule inhibitor of Hsp90

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13067-13067 ◽  
Author(s):  
P. M. Steed ◽  
P. Fadden ◽  
S. Hall
Keyword(s):  
Body Weight ◽  
Natural Product ◽  
Small Molecule ◽  
Clinical Chemistry ◽  
Water Soluble ◽  
Tumor Growth Inhibition ◽  
Hsp90 Inhibition ◽  
Multiple Dosing ◽  
Oral Doses ◽  
Orally Active

13067 Background: The preclinical and clinical data evaluating derivatives of the natural product geldanamycin, including 17-AAG and 17-DMAG, reveal that inhibition of the molecular chaperone HSP90 results in multiple anti-tumor effects. SNX-5422 and SNX-5542 are potent, novel, highly specific, water soluble and orally active small molecule inhibitors of Hsp90. Here we describe the preclinical efficacy and toxicity evaluation of these compounds. Methods: The PK profile of SNX-5422 and SNX-5542 was determined following oral and iv dosing in mice and rats. HT29 xenografts were performed oral doses of SNX-5542 on a schedule of Q2DX3,2 for 2 weeks or 17-DMAG on the previously reported regimen of bid×5,2 for 2 weeks, with tumor progression and body weight monitored. Plasma, tumor and other tissues were harvested for evaluation of HSP70 induction and levels of HSP90 client proteins. Rats were treated with varying oral doses on a schedule of Q2DX3,2 for two weeks. Clinical observations were noted and standard hematology and clinical chemistry parameters were monitored. Results: SNX-5542 exhibited 37% oral BA in rats and >75% in mice, with t½ >7h in each species. SNX-5542 was well tolerated in normal and tumor-bearing mice at 300 mg/m2 Q2DX3,2 for 2 weeks, 0.9% weight gain. 17-DMAG at 30 mg/m2 bid×5,2 for 2 weeks caused 3.3% body weight loss. At these doses, SNX-5542 exhibited 78% median tumor growth inhibition of HT29 tumors while 17-DMAG exhibited 23% inhibition. Mechanistic indicators of HSP90 inhibition correlated with efficacy across multiple dosing levels. At 120 mg/m2 Q2DX3,2 for 2 weeks SNX-5422 was well tolerated in rats, with no significant effect on any clinical, hematology or clinical chemistry parameter with the exception of a slight increase in blood urea nitrogen levels. Histopathological evaluation of liver, thymus, spleen and kidneys revealed no significant treatment-related effects. At 120 mg/m2 Q2DX3,2 for 13 days SNX-5422 does not exhibit any of the toxicities reported for 17-DMAG (bidX5,2 for 8 days at 24 mg/m2). Conclusions: SNX small-molecule HSP90 inhibitors have favorable pharmacokinetic profiles, oral bioavailability, tolerability and superior anti-tumor activity compared to the natural product derivative 17-DMAG. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document