Reference

Assessing and managing toxicities induced by kinase inhibitors

All Rights Reserved. Assessing and managing toxicities induced by kinase inhibitors. Castoldi, Raffaella E.; Pennella, Giulia; Saturno, Grazia S.; Grossi, Pietro; Brughera, Marco; Venturi, Miro (Preclinical Development Attrition Reducing Technologies - Analytical Biology Group, Nerviano Medical Sciences, Milan, Italy). Current Opinion in Drug Discovery & Development, 10(1), 53-57 (English) 2007 Thomson Scientific. 387867-13-2 are also occured in this study. CODEN: CODDFF. ISSN: 1367-6733. DOCUMENT TYPE: Journal; General Review CA Section: 1 (Pharmacology) A review. Currently, several protein kinase-modulating compds. have received market approval across a range of diverse therapeutic indications. Furthermore, a large no. of chem. and biol. protein kinase-modulating compds. are undergoing testing at the preclin. and clin. level. Protein kinases are both major pharmacol. targets and diagnostically useful. Progression of kinase modulators toward clin. viable therapies is aided by a reversible mechanism of action, short treatment durations and patient-compliant administration routes. However, the physiol. role and essential functional activity of protein kinases in many organs and tissues complicates, to different extents, the development of useful, highly potent protein kinase modulators. In this review, we will highlight common problems in the development of these compds. and lessons learned from the extensive preclin. and clin. characterization of some key protein kinase modulators, some of which have either entered and successfully completed clin. trials or have been abandoned as a consequence of unacceptable toxicity issues. We will ultimately explore how mol. profiling tools combined with histopathol. endpoints can be adopted to address and further understand these toxicities in humans and understand their relevance and characterization when identified during early animal expts. .

CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML)

CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Kelly, Louise M.; Yu, Jin-Chen; Boulton, Christina L.; Apatira, Mutiah; Li, Jason; Sullivan, Carol M.; Williams, Ifor; Amaral, Sonia M.; Curley, David P.; Duclos, Nicole; Neuberg, Donna; Scarborough, Robert M.; Pandey, Anjali; Hollenbach, Stanley; Abe, Keith; Lokker, Nathalie A.; Gilliland, D. Gary; Giese, Neill A. (Division of Hematology/Oncology, Brigham and Women's Hospital, Boston, MA 02115, USA). Cancer Cell, 1(5), 421-432 (English) 2002 Cell Press. CODEN: CCAECI. ISSN: 1535-6108. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Up to 30% of acute myelogenous leukemia (AML) patients harbor an activating internal tandem duplication (ITD) within the juxtamembrane domain of the FLT3 receptor, suggesting that it may be a target for kinase inhibitor therapy. For this purpose we have developed CT53518, a potent antagonist that inhibits FLT3, platelet-derived growth factor receptor (PDGFR), and c-Kit (IC50 ~200 nM), while other tyrosine or serine/threonine kinases were not significantly inhibited. In Ba/F3 cells expressing different FLT3-ITD mutants, CT53518 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC50 of 10-100 nM. In human FLT3-ITD-pos. 387867-13-2 is just another one chemical used in this study. AML cell lines, CT53518 induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways. Therapeutic efficacy of CT53518 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease. .