Novel Warheads For Targeted Therapies Of Cancer: The Concept And Design Of Oxime-Ether-Based Pro-Pbds

Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antibiotics are a class of natural products produced by various actinomycetes bacteria. PBD-dimers function as sequence-selective DNA-crosslinking, alkylating compounds which are considerably more potent than systemic chemotherapeutic agents. PBDs recognize and bond to specific sequences in the DNA minor groove. After DNA insertion, a covalent aminal bond is formed through nucleophilic attack of the N-2 of a guanine (G) base on the electrophilic C-11 imine of PBD. The end result is obstruction of tumor cell division without any significant distortion of the DNA9s helical structure, thus potentially avoiding the common phenomenon of drug resistance. In recent years, synthetic PBD-dimers have emerged as a promising class of payloads for conjugates in the field of targeted cancer therapies. Unfortunately, many PBD conjugates preserve the strongly alkylating (electrophilic C-11) imine moiety within their structural framework, which can react in a deleterious manner while in circulation on their way to their intended targets. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine functionality. In our design concept, we replaced this moiety with its synthetic precursors: an aldehyde and an amine. The later provided an attachment point to targeting ligands through self-immolative linker systems, whereas the former was masked as an oxime ether. Such oxime ethers are known to exhibit enhanced stability under physiological conditions. Once the prodrug (pro-PBD) conjugate enters a targeted cell, cleavage of the linker system triggers the generation of an aromatic amine. As we discovered, an intramolecular ring-closure subsequently takes place as the aromatic amine adds directly into the sp 2 center of the oxime ether to form the imine condensate and ultimately the 1,4-diazepine ring in a PBD framework. In our pro-PBDs, we envision exploiting their aromatic amines as a part of an arsenal of self-immolative linker systems for small molecule conjugation. To prove the range of applications for this new class of latent DNA-alkylators, we modified their linkers to tailor the kinetics of prodrug release and drug formation. The utility of these novel warheads and linker systems towards the design of Small Molecule Drug Conjugates (SMDC) for targeted cancer therapies will also be discussed in the presented poster. One can predict that any of the presented pro-PBDs could be easily incorporated as novel payloads in Antibody-Drug Conjugates (ADCs). Citation Format: Iontcho Vlahov, Albert Felten, Ning Zou, Kevin Wang, Hari K. Santhapuram, Paul Kleindl, Spencer Hahn, Jeremy Vaughn, Christopher Leamon. Novel warheads for targeted therapies of cancer: The concept and design of oxime-ether-based pro-PBDs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 757.