Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor-selective treatment approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. Antibody-drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents. The recent approval of two ADCs, brentuximab vedotin and ado-trastuzumab emtansine, for cancer treatment has spurred tremendous research interest in this field. This Review touches upon the early efforts in the field, and describes how the lessons learned from the first-generation ADCs have led to improvements in every aspect of this technology, i.e., the antibody, the cytotoxic compound, and the linker connecting them, leading to the current successes. The design of ADCs currently in clinical development, and results from mechanistic studies and preclinical and clinical evaluation are discussed. Emerging technologies that seek to further advance this exciting area of research are also discussed.

Antibody-drug conjugates: an emerging concept in cancer therapy

DNA Cross-Linking Agents as Antitumor Drugs.

DNA minor-groove recognition by small molecules

Rational approaches, design strategies, structure activity relationship and mechanistic insights for anticancer hybrids

A novel sequence-selective pyrrolobenzodiazepine (PBD) dimer 5 (SJG-136) has been developed that comprises two C2-exo-methylene-substituted DC-81 (3) subunits tethered through their C8 positions via an inert propanedioxy linker. This symmetric molecule is a highly efficient minor groove interstrand DNA cross-linking agent (XL50 = 0.045 muM) that is 440-fold more potent than melphalan, Thermal denaturation studies show that, after 18 h incubation with calf thymus DNA at a 5:1 DNA/ligand ratio, it increases the T-m value by 33.6 degreesC, the highest value so far recorded in this assay. The analogous dimer 4 (DSB-120) that lacks substitution/ unsaturation at the C2 position elevates melting by only 15.1 degreesC under the same conditions, illustrating the effect of introducing C2-exo-unsaturation which serves to flatten the C-rings and achieve a superior isohelical fit within the DNA minor groove. This behavior is supported by molecular modeling studies which indicate that (i) the PBD units are covalently bonded to guanines on opposite strands to form a cross-link, (ii) 5 has a greater binding energy compared to 4, and (iii) 4 and 5 have equivalent binding sites that span six base pairs. Dimer 5 is significantly more cytotoxic than 4 in a number of human ovarian cancer cell lines (e.g., IC50 values of 0.0225 nM vs 7.2 nM, respectively, in A2780 cells). Furthermore, it retains full potency in the cisplatin-resistant cell line A2780cisR (0.024 nM), whereas 4 loses activity (0.21 muM) with a resistance factor of 29.2, This may be due to a lower level of inactivation of 5 by intracellular thiol-containing molecules. A dilactam analogue (21) of 5 that lacks the electrophilic N10-C11/N10'-C11' imine moieties has also been synthesized and evaluated. Although unable to interact covalently with DNA, 21 still stabilizes the helix (DeltaT(m) = 0.78 degreesC) and has significant cytotoxicity in some cell lines (i.e., IC50 = 0.57 muM in CH1 cells), presumably exerting its effect through noncovalent interaction with DNA.

Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity.

Rational design of a highly efficient irreversible DNA interstrand cross-linking agent based on the pyrrolobenzodiazepine ring system

An efficient convergent synthesis of a homologous series of C8-linked pyrrolobenzodiazepine dimers with remarkable DNA interstrand cross-linking activity and potent in vitro cytotoxicity is reported. The “amino thioacetal” cyclization procedure was used to produce the electrophilic DNA-interactive N10−C11 imine moiety during the final synthetic step. In order to construct the key A-ring fragments (9a−d), a versatile convergent approach has been developed to join two units of vanillic acid with α,ω-dihaloalkanes of varying length to provide the required bis(4-carboxy-2-methoxyphenoxy)alkanes while avoiding the formation of mixtures of monoalkylated and bisalkylated products.

D. Subhas Bose

Papers

Rational design of a highly efficient irreversible DNA interstrand cross-linking agent based on the pyrrolobenzodiazepine ring system

Synthesis of Sequence-Selective C8-Linked Pyrrolo[2,1-c][1,4]benzodiazepine DNA Interstrand Cross-Linking Agents.

Sn(III)Cl2-induced regiospecific opening of the 1,3-benzodioxole ring system: A route to the novel DNA-interactive, ligand) iso-DC-81