Discovery of novel polyamide-pyrrolobenzodiazepine hybrids for antibody-drug conjugates.

Autor: Thomas JD; Mersana Therapeutics, 840 Memorial Drive, Cambridge, MA 02139, USA., Yurkovetskiy AV; Formerly Mersana Therapeutics, USA., Yin M; Formerly Mersana Therapeutics, USA., Bodyak ND; Formerly Mersana Therapeutics, USA., Gumerov DR; Formerly Mersana Therapeutics, USA., Tang S; Formerly Mersana Therapeutics, USA., Kelleher E; Mersana Therapeutics, 840 Memorial Drive, Cambridge, MA 02139, USA., Jones BD; Formerly Mersana Therapeutics, USA., Protopopova M; Mersana Therapeutics, 840 Memorial Drive, Cambridge, MA 02139, USA., Qin L; Formerly Mersana Therapeutics, USA., Uttard A; Mersana Therapeutics, 840 Memorial Drive, Cambridge, MA 02139, USA., Demady DR; Formerly Mersana Therapeutics, USA., Lowinger TB; Mersana Therapeutics, 840 Memorial Drive, Cambridge, MA 02139, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2022 Sep 15; Vol. 72, pp. 128876. Date of Electronic Publication: 2022 Jul 03.
DOI: 10.1016/j.bmcl.2022.128876
Abstrakt: Pyrrolobenzodiazepine (PBD) dimers are well-known highly potent antibody drug conjugate (ADC) payloads. The corresponding PBD monomers, in contrast, have received much less attention from the ADC community. We prepared several novel polyamide-linked PBD monomers and evaluated their utility as ADC payloads. The unconjugated polyamide-PBD hybrids exhibited potent antiproliferative activity (IC50 range: 10 -11 -10 -8 M) against a variety of HER2-expressing cancer cell lines. Several peptide-linked variants of the lead compound were prepared and conjugated to trastuzumab to afford ADCs with drug-to-antibody (DAR) ratios ranging from 3 to 5. The ADCs exhibited antigen-dependent cytotoxicity in vitro and potently suppressed tumor xenograft growth in vivo in a target-dependent manner. Moreover, the ADCs were well-tolerated in both mouse and rat. This work demonstrates for the first time that PBD polyamide hybrids can serve as effective ADC payloads.
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Databáze: MEDLINE
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