Design and Synthesis of a Trifunctional Molecular System “Programmed” to Block Epidermal Growth Factor Receptor Tyrosine Kinase, Induce High Levels of DNA Damage, and Inhibit the DNA Repair Enzyme (Poly(ADP-ribose) Polymerase) in Prostate Cancer Cells

Abstract

Resistance to chemotherapy in advanced cancers can be mediated by different factors such as epidermal growth factor receptor (EGFR) overexpression and DNA repair enzymes. Therefore, current standards of care usually involve combinations of multiple treatments. Here, to reduce the adverse effects of multiple drug combinations and improve outcome, we proposed a single drug approach to block multiple overlapping effects that characterize chemoresistance. Thus, we designed a new linker that allows assembly of multiple functions (e.g., inhibition of EGFR phosphorylation, induction of DNA lesions, and blockade of their repair) into a single molecule. This led to the successful synthesis of a novel and potent combi-molecule JS230. Here, we demonstrated that in resistant prostate cancer cells overexpressing EGFR, it was capable of (a) inhibiting EGFR in a dose-dependent manner, (b) damaging DNA, and (c) sustaining the damage by inhibiting the DNA repair protein poly(ADP-ribose) polymerase (PARP). The triple mechanism of action of JS230 cumulated into growth inhibitory potency superior to that of classical two-or three-drug combinations.

Strategies for designing proteolysis targeting chimaeras (PROTACs)

“…Currently, most PROTACs focus on the degradation of a single target or several target subtypes within a protein family. Considering the advantages and success of multitargeting agents and bispecific antibodies, 234,235 designing a PROTAC that can degrade two or more different targets may achieve better therapeutic effects and expand the scope of PROTAC technology. To validate this hypothesis, Li's group designed dual‐targeting PROTACs that simultaneously degraded EGFR and PARP 48 .…”

Rational Design and Synthesis of Novel Dual PROTACs for Simultaneous Degradation of EGFR and PARP

“…They have gradually become an alternative to combination therapy or the use of mixtures. 6,7 Proteolysis targeting chimera (PROTAC) is a kind of bifunctional small molecule, in which the target protein ligand and the E3 ubiquitin ligase ligand are linked together through a linker to form a triplet compound. 8 Compared with traditional small molecule inhibitors, PROTAC has several advantages.…”

“…[11][12] The inhibition of EGFR leads to the down-regulation of key players in BER and sensitizes cell response to alkylating agents and ionizing radiation. [13][14] inhibition of both EGFR and PARP may produce a synergistic effect. [3] In order to verify the concept of dual protac shown above, we designed the first round of dual protac molecules by merging EGFR inhibitors and PARP inhibitors with E3 ligase ligand in one novel star shape molecule, and evaluated their capability to degrade two independent targets at the cellular level.…”

Quantitative Analysis of the Potency of Equimolar Two-Drug Combinations and Combi-Molecules Involving Kinase Inhibitors In Vitro: The Concept of Balanced Targeting

“…Thus, in recent years, strategies designed to overcome resistance mediated by compensatory signaling have involved the use of a multi-targeted approach [4,5]. Within this context, over the past decade, we developed a novel approach termed "combi-targeting" that sought to design agents designated as "combi-molecules" capable of inducing tandem blockade of two divergent biological targets (e.g., EGFR, PARP, MEK, and DNA) [6][7][8][9][10][11][12][13][14][15][16]. Further work on the concept led to the synthesis of molecules rationally designed to target two oncogenic tyrosine kinases involved in adverse signaling [17,18].…”