Abstract 5147: Novel warheads for targeted therapies of cancer: The concept and design of proPBDs

Abstract

Abstract Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antibiotics, are a class of natural products produced by various actinomycetes bacteria. PBDs are sequence selective DNA-crosslinking alkylating compounds and are considerably more potent than systemic chemotherapeutic agents. Some PBDs have the ability to recognize and bond to specific sequences of DNA. After insertion in the minor groove, a covalent aminal bond is formed through nucleophilic attack of the N-2 of a guanine (G) base on the electrophillic C-11 imine of PBD. The end result is obstruction of tumor cell division without any significant distortion of the DNA’s helix, 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 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 conjugated prodrugs lacking the imine moiety. Once the prodrug (proPBD) conjugate enters a targeted cell, cleavage of the linker system in the construct triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine, and as a result, the diazepine ring. In our proPBDs, we envision to mask the aldehyde as a hydrolytically sensitive oxazolidine moiety and to exploit its ring system as a part of an arsenal of self-immolative linker systems for conjugation. To prove the range of applications for this new class of latent DNA-alkylators, we designed and prepared a diverse variety of novel warheads, consisting of proPBD dimers, hybrids of proPBD with other powerful alkylating agents, as well as tethers of proPBDs with sequence-selective DNA minor groove binders. The utility of the so prepared novel warheads in the design of small molecule drug conjugates (SMDC) for targeted cancer therapies will be also discussed in the presented poster. Citation Format: Iontcho Vlahov, Longwu Qi, Spencer Hahn, Kevin Wang, Hari K. Santhapuram, Albert Felten, Paul Kleindl, Jeremy Vaughn, Christopher P. Leamon. Novel warheads for targeted therapies of cancer: The concept and design of proPBDs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5147. doi:10.1158/1538-7445.AM2017-5147