Hybrid Drugs-A Strategy for Overcoming Anticancer Drug Resistance?

Abstract

Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers' molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, indicate that an effective fight against cancer requires a multidimensional approach. Multi-target chemotherapy may be achieved using drugs combination, co-delivery of medicines, or designing hybrid drugs. Hybrid drugs simultaneously targeting many points of signaling networks and various structures within a cancer cell have been extensively explored in recent years. The single hybrid agent can modulate multiple targets involved in cancer cell proliferation, possesses a simpler pharmacokinetic profile to reduce the possibility of drug interactions occurrence, and facilitates the process of drug development. Moreover, a single medication is expected to enhance patient compliance due to a less complicated treatment regimen, as well as a diminished number of adverse reactions and toxicity in comparison to a combination of drugs. As a consequence, many efforts have been made to design hybrid molecules of different chemical structures and functions as a means to circumvent drug resistance. The enormous number of studies in this field encouraged us to review the available literature and present selected research results highlighting the possible role of hybrid drugs in overcoming cancer drug resistance.

Keywords: cancer; conjugate; drug resistance; hybrid drug; overcoming anticancer drug resistance.

Figure 1

Selected platinum(IV) complexes with valproate (1, 2) or 4-PhB (3, 4) axial ligands.

Figure 2

Selected Pt(IV) conjugates with inhibitors of tubulin polymerization.

Figure 3

Chlorambucil Pt(IV) conjugates: CLB-Pt 8 and CLB-Pt-CLB 9.

Figure 4

Structure of quadruple action Pt(IV) complex.

Figure 5

Structure of the most active bifendate-chalcone hybrid against P-gp function.

Figure 6

Selected dual P-gp and CA XII inhibitors.

Figure 7

The most potent THIQ-coumarin conjugate.

Figure 8

Structures of selected 1-aminated thioxantones.

Figure 9

Representative combrestatin A (CA-4) and pironetin hybrid molecules.

Figure 10

The most potent MTX-diosgenin conjugate.

Figure 11

Amphiphilic drug−drug conjugate (ADDC) Ir-Cb, self-assembling into ADDC nanoparticles.

Figure 12

Structure of ethacraplatin (EA-CPT).

Figure 13

The most potent methyltriazene hybrid bearing O⁶-bnzylguanine moiety.

Figure 14

A hybrid compound with dual chloroethylating and methylating functions.

Figure 15

Rrepresentative combi-nitrosourea hybrid.

Figure 16

Structure of Pt-wogonin conjugate.

Figure 17

Structure of Cx-platin hybrid.

Figure 18

Hybrid furo[2,3-d]pyrimidines exhibiting dual antitubulin and antiangiogenic activities.

Figure 19

PT-TKI hybrids. Each TKI (34–36) was conjugated with each platinum derivative (37–39) through nitrogen atom labelled *.

Figure 20

Structure of RapaLink-1.

Figure 21

Structure of dual PI3K and mTOR inhibitor with excellent activity in vivo.

Figure 22

Curcumin-BTP hybrid—a STAT3 inhibitor with reactive oxygen species (ROS)-promoting activity.

Figure 23

CUDC-101 44 consists of a key fragment from the kinase inhibitor 35, tethered by an appropriate linker to a zinc binding group from HDACi-SAHA 43.

Figure 24

Structure of CUDC-907 (Fimepinostat).

Figure 25

Structure of EDO-S101 (Tinostamustine).