398 POSTER Discovery and characterization of a small molecule inhibitor of human Cdc7 kinase

2006 ◽  
Vol 4 (12) ◽  
pp. 122
Author(s):  
C. Santocanale ◽  
A. Montagnoli ◽  
P. Tenca ◽  
M. Menichincheri ◽  
B. Valsasina ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Cdc7 Kinase

scholarly journals Rational design and characterization of a Rac GTPase-specific small molecule inhibitor

2004 ◽  
Vol 101 (20) ◽  
pp. 7618-7623 ◽  
Author(s):  
Y. Gao ◽  
J. B. Dickerson ◽  
F. Guo ◽  
J. Zheng ◽  
Y. Zheng
Keyword(s):  
Small Molecule ◽  
Rational Design ◽  
Small Molecule Inhibitor ◽  
Rac Gtpase ◽  
Molecule Inhibitor

Characterization of BMS-911543, a Functionally Selective Small Molecule Inhibitor of JAK2

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4112-4112 ◽  
Author(s):  
Ashok V Purandare ◽  
Animesh Pardanani ◽  
Theresa McDevitt ◽  
Marco Gottardis ◽  
Terra Lasho ◽  
...  
Keyword(s):  
Small Molecule ◽  
Cell Types ◽  
Small Molecule Inhibitor ◽  
Janus Kinase ◽  
Jak Inhibitors ◽  
In Vivo Models ◽  
Molecule Inhibitor ◽  
Transcriptional Changes ◽  
Dose Levels

Abstract Abstract 4112 We report the characterization of BMS-911543, a potent and functionally selective small molecule inhibitor of the Janus kinase family (JAK) member, JAK2. BMS-911543 is a reversible inhibitor of JAK2 with a biochemical IC50 of 0.001 μ M and Ki of 0.48 nM. It has over 74- and 350-fold selectivity against the other JAK family members, JAK3 and JAK1, respectively. Further, examination of > 450 other kinases did not reveal significant inhibitory activity for this JAK2 inhibitor. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in mutated JAK2-expressing cell lines dependent upon JAK2-STAT signaling and had little activity in cell types dependent upon other pathways such as JAK1 and JAK3. BMS-911543 was evaluated in colony growth assays using primary progenitor cells isolated from patients with JAK2V617F-positive myeloproliferative disease (MPD) and resulted in an increased anti-proliferative response in MPD cells as compared with those from healthy volunteers. Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2-pSTAT signaling in multiple species (mouse, rat, dog and monkey) with sustained pathway suppression being observed after a single oral dose. Additionally, BMS-911543 was evaluated for effects in a JAK2V617F-expressing SET-2 xenograft model system and displayed a minimally effective dose of <2 mg/kg on pSTAT5 pathway suppression, which lasted up to 8 hours. BMS-911543 was also compared to pan-JAK inhibitors in a mouse model of immunosuppression. At low dose levels active in JAK2-dependent PD models, no effects were observed on antigen-induced IgG and IgM production whereas a pan-JAK family inhibitor showed pronounced effects at all dose levels tested. The mechanistic selectivity of BMS-911543 to pan-JAK family inhibitors was extended through comparative analysis of these inhibitors in whole genome gene expression profiling experiments performed in sensitive cell types. In this comparison, BMS-911543 modulated a distinct subset of transcriptional changes as compared to pan-JAK inhibitors, thereby defining a minimal set of transcriptional changes underlying the pharmacologic effects of JAK2 inhibition. Collectively these results define the mechanistic basis for a differential therapeutic index between selective JAK2 and pan-JAK family inhibition pre-clinically and suggest a therapeutic rationale for the further characterization of BMS-911543 in patients with MPD and in other disorders characterized by constitutively active JAK2 signaling. Disclosures: Purandare: Bristol-Myers Squibb: Employment. McDevitt:Bristol-Myers Squibb: Employment. Gottardis:Bristol-Myers Squibb: Employment. You:Bristol-Myers Squibb: Employment. Lombardo:Bristol_Myers Squibb: Employment. Penhallow:Bristol-Myers Squibb: Employment. Vuppugalla:Bristol-Myers Squibb: Employment. Trainor:Bristol-Myers Squibb: Employment. Lorenzi:Bristol-Myers Squibb: Employment.

Pre-clinical characterization of CX-4945, a potent and selective small molecule inhibitor of CK2 for the treatment of cancer

2011 ◽  
Vol 356 (1-2) ◽  
pp. 37-43 ◽  
Author(s):  
Fabrice Pierre ◽  
Peter C. Chua ◽  
Sean E. O’Brien ◽  
Adam Siddiqui-Jain ◽  
Pauline Bourbon ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals Characterization of EHop-016, Novel Small Molecule Inhibitor of Rac GTPase

2012 ◽  
Vol 287 (16) ◽  
pp. 13228-13238 ◽  
Author(s):  
Brenda L. Montalvo-Ortiz ◽  
Linette Castillo-Pichardo ◽  
Eliud Hernández ◽  
Tessa Humphries-Bickley ◽  
Alina De La Mota-Peynado ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Rac Gtpase ◽  
Molecule Inhibitor

scholarly journals Pharmacological characterization of GLPG1972/S201086, a potent and selective small molecule inhibitor of ADAMTS5

2021 ◽  
Author(s):  
Philippe Clement-Lacroix ◽  
Christopher B. Little ◽  
Margaret M. Smith ◽  
Céline Cottereaux ◽  
Didier Merciris ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Pharmacological Characterization ◽  
Molecule Inhibitor
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