Allosteric cross-talk in chromatin can mediate drug-drug synergy

Abstract

Exploitation of drug–drug synergism and allostery could yield superior therapies by capitalizing on the immensely diverse, but highly specific, potential associated with the biological macromolecular landscape. Here we describe a drug–drug synergy mediated by allosteric cross-talk in chromatin, whereby the binding of one drug alters the activity of the second. We found two unrelated drugs, RAPTA-T and auranofin, that yield a synergistic activity in killing cancer cells, which coincides with a substantially greater number of chromatin adducts formed by one of the compounds when adducts from the other agent are also present. We show that this occurs through an allosteric mechanism within the nucleosome, whereby defined histone adducts of one drug promote reaction of the other drug at a distant, specific histone site. This opens up possibilities for epigenetic targeting and suggests that allosteric modulation in nucleosomes may have biological relevance and potential for therapeutic interventions.

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

“…firstly found that the RAPTA-T can combine with auranofin to yield a synergistic activity in killing cancer cells via the allosteric cross-talk in chromatin. 172 In addition, the RAPTA derivatives inhibited the activity of glutathione transferase, lysozyme, cathepsin B (Cat B) and TrxR. 173 Thus, RAPTA complexes can readily react with proteins and inhibit enzymes, but there is no significant correlation between this reactivity and toxicity in cancer cells.…”

Recent Considerations in the Application of RAPTA‐C for Cancer Treatment and Perspectives for Its Combination with Immunotherapies

“…[77] Further, RAPTA-T has been shown to induce allosteric binding of other drugs in the nucleosome core particle thereby mediating drug-drug synergies. [78] In vivo experiments in the chorioallantoic membrane of the chicken embryo (CAM) and in a CBA mouse model revealed that RAPTA-T reduces the tumor burden of invasive cancer types. [77] Along with RAPTA-C, RAPTA-T exerts anti-metastatic activity and adds another valuable and efficient representative to the family of RAPTA compounds.…”

“…[100][101][102] Several studies describe the use of RAPTA-C in combination with other drugs. [12,13,73,74,78] It appears, especially in in vitro settings, that Ru-based products exceed the efficacy of Pt-based regimens and might provide a better safety profile for prospective clinical use. This effect arises from the blockade of receptor phosphorylation, further inhibiting the activation of the kinase cascade.…”

Crosslinking Allosteric Sites on the Nucleosome

“…[2][3][4] Thea cidic patch is vital for folding the nucleosome into chromatin fiber,the repression of transcription and as the docking area for regulatory proteins. [8][9][10][11][12][13][14] RAPTA-T is an antimetastatic drug, with inhibitory properties towards both primary and metastatic tumors, [15,16] and displays strong site selectivity towards the acidic patch at binding sites consisting of carboxylate groups E61 and E64 on H2A (RU1) and imidazole H106 and carboxylate E102 groups on H2B (RU2). [8][9][10][11][12][13][14] RAPTA-T is an antimetastatic drug, with inhibitory properties towards both primary and metastatic tumors, [15,16] and displays strong site selectivity towards the acidic patch at binding sites consisting of carboxylate groups E61 and E64 on H2A (RU1) and imidazole H106 and carboxylate E102 groups on H2B (RU2).…”

“…[4][5][6][7] Thea cidic patch plays host to at least two specific metal binding sites belonging to RAPTA-T,[ h 6 -p-toluene)Ru(1,3,5-triaza-7phosphaadamantane)Cl 2 ] ( Figure 1), and auranofin, [(3,4,5triacetyloxy-6-acteyloxymethyl,oxane-2-thio-late)Au(triethylphosphanium)] (AUF, Figure 1). [13] TheR U1 and RU2s ites have been crosslinked by binuclear RAPTA-like complexes linked via the arene using av ariety of rigid and flexible linkers that strongly influence the nature of the crosslink. [13] TheR U1 and RU2s ites have been crosslinked by binuclear RAPTA-like complexes linked via the arene using av ariety of rigid and flexible linkers that strongly influence the nature of the crosslink.…”