The pyrrolo[2,1‐c][1,4]benzodiazepines (PBDs) are a family of sequence‐selective DNA minor‐groove binding agents that form a covalent aminal bond between their C11‐position and the C2‐NH₂groups of guanine bases. The first example of a PBD monomer, the natural product anthramycin, was discovered in the 1960s, and the best known PBD dimer, SJG‐136 (also known as SG2000, NSC 694501 or BN2629), was synthesized in the 1990s and has recently completed Phase II clinical trials in patients with leukaemia and ovarian cancer. More recently, PBD dimer analogues are being attached to tumor‐targeting antibodies to create antibody–drug conjugates (ADCs), a number of which are now in clinical trials, with many others in pre‐clinical development. This Review maps the development from anthramycin to the first PBD dimers, and then to PBD‐containing ADCs, and explores both structure–activity relationships (SARs) and the biology of PBDs, and the strategies for their use as payloads for ADCs.

Antibody drug conjugates (ADCs) are powerful anti-cancer therapies comprising an antibody joined to a cytotoxic payload through a chemical linker. ADCs exploit the specificity of antibodies for their target antigens, combined with the potency of cytotoxic drugs, to selectively kill target antigen-expressing tumour cells. The recent rapid advancement of the ADC field has so far yielded twelve and eight ADCs approved by the US and EU regulatory bodies, respectively. These serve as effective targeted treatments for several haematological and solid tumour types. In the development of an ADC, the judicious choice of an antibody target antigen with high expression on malignant cells but restricted expression on normal tissues and immune cells is considered crucial to achieve selectivity and potency while minimising on-target off-tumour toxicities. Aside from this paradigm, the selection of an antigen for an ADC requires consideration of several factors relating to the expression pattern and biological features of the target antigen. In this review, we discuss the attributes of antigens selected as targets for antibodies used in clinically approved ADCs for the treatment of haematological and solid malignancies. We discuss target expression, functions, and cellular kinetics, and we consider how these factors might contribute to ADC efficacy.

Human telomeric DNA (hTelo), present at the ends of chromosomes to protect their integrity during cell division, comprises tandem repeats of the sequence d(TTAGGG) which is known to form a G-quadruplex secondary structure. This unique structural formation of DNA is distinct from the well-known helical structure that most genomic DNA is thought to adopt, and has recently gained prominence as a molecular target for new types of anticancer agents. In particular, compounds that can stabilize the intramolecular G-quadruplex formed within the human telomeric DNA sequence can inhibit the activity of the enzyme telomerase which is known to be upregulated in tumor cells and is a major contributor to their immortality. This provides the basis for the discovery and development of small molecules with the potential for selective toxicity toward tumor cells. This review summarizes the various families of small molecules reported in the literature that have telomeric quadruplex stabilizing properties, and assesses the ...

Purpose: Anti-EGFR antibodies show limited response in breast cancer, partly due to activation of compensatory pathways. Furthermore, despite the clinical success of cyclin-dependent kinase (CDK) 4/6 inhibitors in hormone receptor–positive tumors, aggressive triple-negative breast cancers (TNBC) are largely resistant due to CDK2/cyclin E expression, whereas free CDK2 inhibitors display normal tissue toxicity, limiting their therapeutic application. A cetuximab-based antibody drug conjugate (ADC) carrying a CDK inhibitor selected based on oncogene dysregulation, alongside patient subgroup stratification, may provide EGFR-targeted delivery. Experimental Design: Expressions of G1/S-phase cell cycle regulators were evaluated alongside EGFR in breast cancer. We conjugated cetuximab with CDK inhibitor SNS-032, for specific delivery to EGFR-expressing cells. We assessed ADC internalization and its antitumor functions in vitro and in orthotopically grown basal-like/TNBC xenografts. Results: Transcriptomic (6,173 primary, 27 baseline, and matched post-chemotherapy residual tumors), single-cell RNA sequencing (150,290 cells, 27 treatment-naïve tumors), and spatial transcriptomic (43 tumor sections, 22 TNBCs) analyses confirmed expression of CDK2 and its cyclin partners in basal-like/TNBCs, associated with EGFR. Spatiotemporal live-cell imaging and super-resolution confocal microscopy demonstrated ADC colocalization with late lysosomal clusters. The ADC inhibited cell cycle progression, induced cytotoxicity against high EGFR-expressing tumor cells, and bystander killing of neighboring EGFR-low tumor cells, but minimal effects on immune cells. Despite carrying a small molar fraction (1.65%) of the SNS-032 inhibitor, the ADC restricted EGFR-expressing spheroid and cell line/patient-derived xenograft tumor growth. Conclusions: Exploiting EGFR overexpression, and dysregulated cell cycle in aggressive and treatment-refractory tumors, a cetuximab–CDK inhibitor ADC may provide selective and efficacious delivery of cell cycle–targeted agents to basal-like/TNBCs, including chemotherapy-resistant residual disease.