Novel, Differentiated Antibody Drug Conjugate Warheads from Analysis of the NCI Screening Database

Abstract

Antibody-drug conjugates (ADCs) combine the selective nature of targeted therapies with potent cytotoxic warheads utilising linker technology to deliver selectively the warhead to the target. Proof of concept has already been observed with five licensed ADCs on the market, giving confidence to the use of ADCs in cancer treatment, with multiple ADCs in clinical testing. Many of these ADCs consist of cytotoxic payloads derived from complex natural products, consequently leading to synthetically long and complicated routes. To address this problem, novel warheads have been identified through screening the NCI database, that are structurally simpler drugs with differing cellular activity profiles. This may also address resistance issues. Out of the seven that were identified, three series have been explored; the nitroacridines (113), the quinolones (106) and thiosemicarbazones (174). Nitroacridines inherently target hypoxic cells and are known to intercalate with DNA. Quinolones are known tubulin binders and compounds synthesised have been evaluated in biological studies. Thiosemicarbazones are metal chelators, sequestering iron and copper. They inhibit ribonucleotide reductase, inactivating the enzyme leading to cell death. Work has been carried out to optimise and resynthesize these parent warheads as well as analogues. The warheads have been coupled to non-cleavable and cleavable dipeptide linkers (examples shown below) and subsequent conjugation to an antibody, which have been assessed in cell assays.