Synergistic drug combinations tend to improve therapeutically relevant selectivity

Abstract

Prevailing drug discovery approaches focus on compounds with molecular selectivity, inhibiting disease-relevant targets over others in vitro. However in vivo, many such agents are not therapeutically selective, either because of undesirable activity at effective doses or because the biological system responds to compensate. In theory, drug combinations should permit increased control of such complex biology, but there is a common concern that therapeutic synergy will generally be mirrored by synergistic side-effects. Here we provide evidence, from 94,110 multi-dose combination experiments representing diverse disease areas and large scale flux balance simulations of inhibited bacterial metabolism, that multi-target synergies are more specific than single agent activities to particular cellular contexts. Using an anti-inflammatory combination, we show how multi-target synergy can achieve therapeutic selectivity in animals through differential target expression. Synergistic combinations can increase the number of selective therapies using the current pharmacopeia, and offer opportunities for more precise control of biological systems.

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

“…In addition, it is proposed to start a study to treat AD patients with vorinostat (Benito et al, 2015), the first HDACi approved for cancer (Mann et al, 2007). However, besides the toxicity associated with strong inhibition of HDAC class I isoforms (Robers et al, 2015), a single-target drug may only produce limited benefits in complex diseases like AD and, indeed, network models suggest that the partial and simultaneous inhibition of different targets is likely to produce more efficient effects than the use of specific and high-affinity inhibitors (Lehar et al, 2009;Zheng et al, 2014). Interestingly, we had empirically validated the beneficial synergistic effect of concomitant HDAC and PDE5 inhibition in AD mice using reference compounds (vorinostat and tadalafil) (Cuadrado-Tejedor et al, 2015).…”

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

“…Most importantly, the combination of multiple therapeutic agents must generate a synergistic effect, ideally at lower doses than typical doses of each individual compound (Fig. 3) [140,141]. Two drugs are synergistic when the combinatorial efficacy is greater than that of the sum of the individual agents.…”

Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma

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