| Over the past two decades, novel targets for anticancer agents have been identified. One such target, the epidermal growth factor receptor (EGFR) that is overexpressed in a large number of carcinomas including breast, ovarian, and prostate, is a marker for tumour invasiveness and poor prognosis. Agents of the quinazoline class have been developed that block EGFR-mediated signaling and induce antitumour activity in the clinic. However, the major deficiency of these compounds is that they are cytostatic agents that induce reversible antiproliferative activities. To circumvent these problems, we designed a novel tumour targeting approach termed "the combi-targeting" concept. This theory is based on the fundamental premise that compounds capable of interfering with multiple targets in the cancer cells are more efficient antitumour agents than the single-targeted ones. Thus, the "combi-targeting" concept proposes the design of molecules termed "combi-molecules" or TZ-I to not only bind to the tumour target but also to be allowed to degrade to another inhibitor I of the same target + a DNA damaging species TZ, leading to small molecules capable of repetitively blocking one target while damaging another. Using EGFR as a tumour target, the first TZ-I prototype SMA41, an anilinoquinazoline containing a triazene tail at the 6-position, was synthesized. We demonstrate herein that the compound enters the cell by passive diffusion, degrades under physiological conditions to yield an intact TK inhibitor ("SMA52") (I) + a short-lived DNA-damaging methyldiazonium species (TZ). In the EGFR-expressing human tumour cells, SMA41 (TZ-I) behaved as a binary targeted drugs with ability to: (a) inhibit EGF-induced receptor autophosphorylation, cell cycle progression and growth, (b) induce dose-dependent DNA damage, and (c) inhibit cell proliferation with greater potency than the released reversible inhibitor (I) both in vitro and in vivo. This work represents the first demonstration of the feasibility of a small molecular system "programmed" to bind to a validated tumour target, degrade to a second inhibitor of the same target and another species capable of damaging a secondary target ( e.g. DNA). Thus, studies performed within the framework of the "combi-targeting" concept have perhaps given rise to the first oncogene-targeted unimolecular mimic of classical multidrug combination therapy. |
