Analogues of Duocarmycin Antibody-Drug Conjugates
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ANALOGUES OF DUOCARMYCIN
Newly synthesised analogues of duocarmycin utilised as an optimised toxic payload in ADCs for cancer treatment.
ADCs are a therapeutic strategy utilising the selectivity of an antibody to deliver an active small molecule to antigen-presenting cells. The majority of ADCs employ toxic payloads that interferes with microtubules, however, DNA minor groove alkylating agents are a suitable alternative; offering extreme cytotoxic potency while being insensitive to many cellular resistance mechanisms. Duocarmycin are a small group of antitumour and antibiotic natural products with extreme cytotoxicity. Currently, some analogues of this compound have been synthesised to arm antitumour antibodies, but are highly lipophilic.
Lipophilic payloads causes aggregation and reduction of the drug-antibody ratio, as well as faster clearance of the resulting ADC. This reduces its overall exposure, eliciting a limited therapeutic response. Therefore, optimisation can been succeded by the minimisation of lipophilicity to maintain cytotoxic potency and modulate the stability. Two different alkylating subunits have been incorporated in to the analogous compound to decrease the lipophilicity.
ADCs are a rapidly emerging class of cancer treatment, therefore, with modified potency, efficacy and stability, duocarmycins could be integrated into existing or future modes of therapy for enhanced ameliorative outcomes.
• Cytotoxic at all phases of the cell cycle and insensitive to drug resistance mechanisms
• Decreased lipophilicity minimises any issues with protein conjugation and faster clearance
• Limiting the aggregation minimises the threats of in vivo immune response, unexpected toxicity, and decreased therapeutic effect
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Contact Dr Sandhya Badrinarayanan