Current strategies to produce homogeneous antibody-drug conjugates (ADCs) rely on mutations or inefficient conjugation chemistries. Here we present a strategy to produce site-specific ADCs using a ...highly reactive natural buried lysine embedded in a dual variable domain (DVD) format. This approach is mutation free and drug conjugation proceeds rapidly at neutral pH in a single step without removing any charges. The conjugation chemistry is highly robust, enabling the use of crude DVD for ADC preparation. In addition, this strategy affords the ability to precisely monitor the efficiency of drug conjugation with a catalytic assay. ADCs targeting HER2 were prepared and demonstrated to be highly potent and specific in vitro and in vivo. Furthermore, the modular DVD platform was used to prepare potent and specific ADCs targeting CD138 and CD79B, two clinically established targets overexpressed in multiple myeloma and non-Hodgkin lymphoma, respectively.
Highly enantio‐ and diastereoselective (Ipc)2BOTf mediated aldol reactions of morpholine carboxamides are described. A wide variety of α‐substituted N‐acyl morpholine carboxamides were successfully ...employed, including α‐bromo, α‐chloro, α‐vinyl and para‐methoxyphenyl morpholine carboxamides which provided the corresponding aldol products in moderate to excellent yields, and generally with high enantio‐ and diastereoselectivities.
The goal of our project is to synthesize a dual CXCR4/CCR5 co‐receptor inhibitor to block the entry of HIV into host cells.
In the early phase of the HIV‐1 replication cycle, HIV‐1 binds to host ...cells through the CD4 protein present on the host cell surface. To infect the cell, HIV‐1 requires further interactions that promote fusion of the viral and cellular membranes. This can occur through binding to the chemokine co‐receptors such as CXCR4 and CCR5. We are choosing dual inhibition since under selective pressure of a CCR5 antagonist, CXCR4‐using strains have been shown to predominate. Through dual inhibition, we want to account for a possible resistance development that could occur when inhibiting only one of the two co‐receptors.
Using a computational screen, a compound predicted to bind to both CCR5 and CXCR4 was identified (Hit 1). We established a reaction scheme to synthesize an analog of this compound (target compound 4) through solid phase peptide synthesis (Scheme 1). We completed the synthesis of compound 4 and we confirmed the addition of the first two amino acids (Fmoc‐phenylalanine and Fmoc‐proline) through LC‐MS and HPLC.
We are currently expecting LC‐MS and HPLC results for the rest of the synthesis steps. Before the time of presentation, we plan to use our established methodology to synthesize multiple analogs through varying amino acids and evaluate them for biological activity. The goal of synthesizing analogs is to optimize CXCR4/CCR5 dual inhibition.
While all clinically translated antibody-drug conjugates (ADCs) contain a single-drug payload, most systemic cancer chemotherapies involve use of a combination of drugs. These regimens improve ...treatment outcomes and slow development of drug resistance. We here report the generation of an ADC with a dual-drug payload that combines two distinct mechanisms of action.
Virtual DNA crosslinking agent PNU-159682 and tubulin polymerization inhibitor monomethyl auristatin F (MMAF) were conjugated to a HER2-targeting antibody
site-specific conjugation at engineered selenocysteine and cysteine residues (thio-selenomab).
The dual-drug ADC showed selective and potent cytotoxicity against HER2-expressing cell lines and exhibited dual mechanisms of action consistent with the attached drugs. While PNU-159682 caused S-phase cell cycle arrest due to its DNA-damaging activity, MMAF simultaneously inhibited tubulin polymerization and caused G2/M-phase cell cycle arrest.
The thio-selenomab platform enables the assembly of dual-drug ADCs with two distinct mechanisms of action.
Abstract
Highly enantio‐ and diastereoselective (Ipc)
2
BOTf mediated aldol reactions of morpholine carboxamides are described. A wide variety of α‐substituted
N
‐acyl morpholine carboxamides were ...successfully employed, including α‐bromo, α‐chloro, α‐vinyl and
para‐
methoxyphenyl morpholine carboxamides which provided the corresponding aldol products in moderate to excellent yields, and generally with high enantio‐ and diastereoselectivities.
Conventional antibody-drug conjugates (ADCs) are heterogeneous mixtures that have poor pharmacokinetic properties and decreased efficacy relative to homogenous ADCs. Furthermore, ADCs that are ...maleimide-based often have inadequate circulatory stability, which can result in premature drug release with consequent off-target toxicities. Selenocysteine-modified antibodies have been developed that allow site-specific antibody conjugation, yielding homogeneous ADCs. Herein, we survey several electrophilic functional groups that react with selenocystine with high efficiency. Several of these result in conjugates with stabilities that are superior to maleimide conjugates. Among these, the allenamide functional group reacts with notably high efficiency, leads to conjugates with remarkable stability, and shows exquisite selectivity for selenocysteine conjugation.
Site-specific conjugation technologies enable the production of homogeneous antibody–drug conjugates (ADCs) with improved therapeutic indices compared to conventional ADCs. However, current ...site-specific conjugation methods can only attach one type of drug to a single antibody. Given the emergence of acquired resistance to current ADCs, arming single antibodies with different drugs may provide an attractive option in the development of next-generation ADCs. Here, we describe a site-specific dual conjugation strategy as a platform for dual warhead ADCs.
The Suzuki–Miyaura cross-coupling reaction of cyclic ketene acetal phosphates with arylboronic acids was found to be a convenient and highly efficient method for the construction of aryl vinyl ...ethers. A wide variety of differentially substituted electron-poor and electron-rich arylboronic acids smoothly underwent the coupling process to provide the desired dihydropyrans in moderate to excellent yields.
The Suzuki–Miyaura cross-coupling reaction of cyclic ketene acetal phosphates with arylboronic acids was found to be a convenient and highly efficient method for the construction of aryl vinyl ethers. A wide variety of differentially substituted electron-poor and electron-rich arylboronic acids smoothly underwent the coupling process to provide the desired dihydropyrans in moderate to excellent yields.
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