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1.
Mol Cancer Ther ; 22(9): 999-1012, 2023 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-37294948

RESUMO

Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 is a site-specific DS DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a phase I study (NCT05377996) in patients with cancer.


Assuntos
Antineoplásicos , Neoplasias da Mama , Imunoconjugados , Humanos , Feminino , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Anticorpos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Org Chem ; 83(11): 6110-6126, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29786446

RESUMO

An effective late-stage large-fragment union/rearrangement exploiting the Petasis-Ferrier protocol, in conjunction with multicomponent Type I Anion Relay Chemistry (ARC) to access advanced intermediates, permits completion of a convergent, stereocontrolled total synthesis of the architecturally complex phosphomacrolide (-)-enigmazole A (1).


Assuntos
Macrolídeos/síntese química , Compostos Organofosforados/síntese química , Oxazóis/síntese química , Ciclização , Concentração de Íons de Hidrogênio , Estrutura Molecular , Oxirredução , Estereoisomerismo , Temperatura
3.
J Am Chem Soc ; 137(49): 15426-9, 2015 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-26632969

RESUMO

A highly convergent, stereocontrolled total synthesis of the architecturally complex marine sponge metabolite (-)-enigmazole A has been achieved. Highlights include an unprecedented late-stage large-fragment Petasis-Ferrier union/rearrangement, a multicomponent Type I Anion Relay Chemistry (ARC) tactic, and a dithiane-epoxide union in conjunction with an oxazole-directed stereoselective reduction.


Assuntos
Macrolídeos/síntese química , Compostos Organofosforados/síntese química , Oxazóis/síntese química , Macrolídeos/química , Estrutura Molecular , Compostos Organofosforados/química , Oxazóis/química
4.
Chem Commun (Camb) ; (24): 3047-9, 2005 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-15959580

RESUMO

The adjacent centres of electrophilicity and nucleophilicity lead to interesting chemical reactivity in the title reagent.

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