ABSTRACT
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.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Immunoconjugates , Humans , Female , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antibodies , Cell Line, Tumor , Xenograft Model Antitumor AssaysABSTRACT
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).
Subject(s)
Macrolides/chemical synthesis , Organophosphorus Compounds/chemical synthesis , Oxazoles/chemical synthesis , Cyclization , Hydrogen-Ion Concentration , Molecular Structure , Oxidation-Reduction , Stereoisomerism , TemperatureABSTRACT
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.
Subject(s)
Macrolides/chemical synthesis , Organophosphorus Compounds/chemical synthesis , Oxazoles/chemical synthesis , Macrolides/chemistry , Molecular Structure , Organophosphorus Compounds/chemistry , Oxazoles/chemistryABSTRACT
The adjacent centres of electrophilicity and nucleophilicity lead to interesting chemical reactivity in the title reagent.
