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1.
ACS Med Chem Lett ; 10(12): 1674-1679, 2019 Dec 12.
Article in English | MEDLINE | ID: mdl-31857845

ABSTRACT

Targeted antimitotic agents are a promising class of anticancer therapies. Herein, we describe the development of a potent and selective antimitotic Eg5 inhibitor based antibody-drug conjugate (ADC). Preliminary studies were performed using proprietary Eg5 inhibitors which were conjugated onto a HER2-targeting antibody using maleimido caproyl valine-citrulline para-amino benzocarbamate, or MC-VC-PABC cleavable linker. However, the resulting ADCs lacked antigen-specificity in vivo, probably from premature release of the payload. Second-generation ADCs were then developed, using noncleavable linkers, and the resulting conjugates (ADC-4 and ADC-10) led to in vivo efficacy in an HER-2 expressing (SK-OV-3ip) mouse xenograft model while ADC-11 led to in vivo efficacy in an anti-c-KIT (NCI-H526) mouse xenograft model in a target-dependent manner.

2.
Org Lett ; 16(15): 3922-5, 2014 Aug 01.
Article in English | MEDLINE | ID: mdl-25032897

ABSTRACT

Thioester-mediated peptide bond formation has recently garnered a lot of attention, most notably in its relevance to condensation of large peptide fragments. Herein, a simple and general ligation method for the preparation of linear and cyclic peptides, starting from peptide thioester, mainly p-chlorophenyl, precursors is reported. The inherent advantages of this method are the low epimerization, reduced dimerization, use of mild reaction conditions, and elimination of superfluous coupling reagents.


Subject(s)
Peptides, Cyclic/chemical synthesis , Peptides/chemistry , Peptides/chemical synthesis , Sulfur Compounds/chemistry , Esters , Molecular Structure , Peptides, Cyclic/chemistry
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