The work, published in the journal Nature Chemistry, will allow the use of natural products that until now have been discarded due to their toxicity
Orthoquinones are highly reactive substances that can be delivered to tumour tissues by conjugation to therapeutic antibodies in a safe and selective manne
“This research opens a window of opportunity in clinical development of highly active compounds that until now were discarded due to their high systemic toxicity”, explains Gonzalo Jiménez Osés, Ikerbasque researcher at CIC bioGUNE, who adds “now they can be used to be delivered to tumour tissues by conjugating them to therapeutic antibodies in a safe and selective manner known as Antibody Drug Conjugates (ADCs)”.
The success of the work, which has been published in Nature Chemistry, lies in the discovery of a new chemical reaction for the controlled release of orthoquinone-type cytotoxic drugs (derivatives of β-lapachone, dunnione and cryptotanshinone) under enzymatic stimulation in acidic conditions typical of tumour environments. The drug-antibody conjugates developed in this work have shown in vivo efficacy against a murine xenograft model of acute myeloid leukaemia.
The application of new chemical entities with innovative mechanisms of action are necessary for the development of next-generation therapies. Natural products are often a source of anticancer agents. However, many natural products identified with medicinal value in vitro remain unexploited due to their high toxicity in vivo. Using the novel protection/conjugation and deprotection/release strategy centred on a previously undescribed pH-sensitive self-immolative 1,6-elimination reaction of the medium, it has been possible to mask this toxicity until the precise moment of release into the tumour tissue targeted by the treatment.
The most obvious potential application of the concepts presented in this research is in the development of targeted cancer drugs and therapies.
The work has been carried out by Gonzalo Jiménez Osés’ research group (CIC bioGUNE), in collaboration with the University of Cambridge, Universidade de Lisboa, AstraZeneca and University Jena.