A Novel DNA Sequence-Selective Guanine Mono-Alkylating ADC Payload Suitable for Solid Tumour Treatment

TY - JOUR

T1 - A Novel DNA Sequence-Selective Guanine Mono-Alkylating ADC Payload Suitable for Solid Tumour Treatment

AU - Andriollo, Paolo

AU - Jackson, Paul

AU - Hasan, Md. Mahbub

AU - Pysz, Ilona

AU - Procopiou, George

AU - Fox, Keith R

AU - Rahman, Miraz

AU - Thurston, David

PY - 2025/3/11

Y1 - 2025/3/11

N2 - Pyridinobenzodiazepines (PDDs) are a new class of DNA mono-alkylating Antibody-Drug Conjugate (ADC) payloads that can be linked through their C9 position to a sequence recognition component, guiding them to specific DNA sequences. Compound 18 is a PDD monomer with a unique sequence-selectivity profile and high cytotoxicity in vitro (e.g., IC50 = 0.30 nM in SW60; 1.6 nM in LIM1215 and 0.142 nM in SW48 cell line, after 96 hours incubation). To evaluate its potential as an ADC payload, an amine functionality was introduced into the terminal phenyl ring, and the modified compound was conjugated to trastuzumab (Drug-Antibody Ratio [DAR] = 1.6). The resulting ADC exhibits significant in vivo efficacy in a pancreatic cancer xenograft model using BALB-c mice transplanted with the CAPAN-1 cell line. Complete tumour regression is observed out to 60 days after a single dose of 2 mg/kg comparing favourably to a 10 mg/kg dose of trastuzumab deruxtecan (Enhertu®). The novel ADC has a good tolerability profile, with a Maximum Tolerated Dose (MTD) above 15 mg/kg. The tolerability and efficacy profile of compound 18 in an ADC format suggests that PDDs represent a potentially valuable new class of payloads for the treatment of solid tumours.

AB - Pyridinobenzodiazepines (PDDs) are a new class of DNA mono-alkylating Antibody-Drug Conjugate (ADC) payloads that can be linked through their C9 position to a sequence recognition component, guiding them to specific DNA sequences. Compound 18 is a PDD monomer with a unique sequence-selectivity profile and high cytotoxicity in vitro (e.g., IC50 = 0.30 nM in SW60; 1.6 nM in LIM1215 and 0.142 nM in SW48 cell line, after 96 hours incubation). To evaluate its potential as an ADC payload, an amine functionality was introduced into the terminal phenyl ring, and the modified compound was conjugated to trastuzumab (Drug-Antibody Ratio [DAR] = 1.6). The resulting ADC exhibits significant in vivo efficacy in a pancreatic cancer xenograft model using BALB-c mice transplanted with the CAPAN-1 cell line. Complete tumour regression is observed out to 60 days after a single dose of 2 mg/kg comparing favourably to a 10 mg/kg dose of trastuzumab deruxtecan (Enhertu®). The novel ADC has a good tolerability profile, with a Maximum Tolerated Dose (MTD) above 15 mg/kg. The tolerability and efficacy profile of compound 18 in an ADC format suggests that PDDs represent a potentially valuable new class of payloads for the treatment of solid tumours.

U2 - 10.1039/D4MD01040J

DO - 10.1039/D4MD01040J

M3 - Article

SN - 2632-8682

SP - 1

EP - 22

JO - RSC Medicinal Chemistry

JF - RSC Medicinal Chemistry

ER -