Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy.

BRAF-targeted kinase inhibitors (KIs) are used to treat malignancies including BRAF-mutant non-small cell lung cancer, colorectal cancer, anaplastic thyroid cancer, and, most prominently, melanoma. However, KI selection criteria in patients remain unclear, as are pharmacokinetic/pharmacodynamic (PK/PD) mechanisms that may limit context-dependent efficacy and differentiate related drugs. To address this issue, we imaged mouse models of BRAF-mutant cancers, fluorescent KI tracers, and unlabeled drug to calibrate in silico spatial PK/PD models. Results indicated that drug lipophilicity, plasma clearance, faster target dissociation, and, in particular, high albumin binding could limit dabrafenib action in visceral metastases compared to other KIs. This correlated with retrospective clinical observations. Computational modeling identified a timed strategy for combining dabrafenib and encorafenib to better sustain BRAF inhibition, which showed enhanced efficacy in mice. This study thus offers principles of spatial drug action that may help guide drug development, KI selection, and combination.

A click-flipped enzyme substrate boosts the performance of the diagnostic screening for Hunter syndrome.

We report on the unexpected finding that click modification of iduronyl azides results in a conformational flip of the pyranose ring, which led to the development of a new strategy for the design of superior enzyme substrates for the diagnostic assaying of iduronate-2-sulfatase (I2S), a lysosomal enzyme related to Hunter syndrome. Synthetic substrates are essential in testing newborns for metabolic disorders to enable early initiation of therapy. Our click-flipped iduronyl triazole showed a remarkably better performance with I2S than commonly used O-iduronates. We found that both O- and triazole-linked substrates are accepted by the enzyme, irrespective of their different conformations, but only the O-linked product inhibits the activity of I2S. Thus, in the long reaction times required for clinical assays, the triazole substrate substantially outperforms the O-iduronate. Applying our click-flipped substrate to assay I2S in dried blood spots sampled from affected patients and random newborns significantly increased the confidence in discriminating between these groups, clearly indicating the potential of the click-flip strategy to control the biomolecular function of carbohydrates.

Modular Nanoparticulate Prodrug Design Enables Efficient Treatment of Solid Tumors Using Bioorthogonal Activation.

Prodrug strategies that facilitate localized and controlled activity of small-molecule therapeutics can reduce systemic exposure and improve pharmacokinetics, yet limitations in activation chemistry have made it difficult to assign tunable multifunctionality to prodrugs. Here, we present the design and application of a modular small-molecule caging strategy that couples bioorthogonal cleavage with a self-immolative linker and an aliphatic anchor. This strategy leverages recently discovered in vivo catalysis by a nanoencapsulated palladium compound (Pd-NP), which mediates alloxylcarbamate cleavage and triggers release of the activated drug. The aliphatic anchor enables >90% nanoencapsulation efficiency of the prodrug, while also allowing >104-fold increased cytotoxicity upon prodrug activation. We apply the strategy to a prodrug formulation of monomethyl auristatin E (MMAE), demonstrating its ability to target microtubules and kill cancer cells only after selective activation by Pd-NP. Computational pharmacokinetic modeling provides a mechanistic basis for the observation that the nanotherapeutic prodrug strategy can lead to more selective activation in the tumor, yet in a manner that is more sensitive to variable enhanced permeability and retention (EPR) effects. Combination treatment with the nanoencapsulated MMAE prodrug and Pd-NP safely blocks tumor growth, especially when combined with a local radiation therapy regimen that is known to improve EPR effects, and represents a conceptual step forward in prodrug design.

Ion-Size-Dependent Formation of Mixed Titanium/Lanthanide Oxo Clusters.

The mixed-metal oxo clusters LnTi4O3(OiPr)2(OMc)11 (Ln = La, Ce; OMc = methacrylate), Ln2Ti6O6(OMc)18(HOiPr) (Ln = La, Ce, Nd, Sm) and Ln2Ti4O4(OMc)14(HOMc)2 (Ln = Sm, Eu, Gd, Ho) have been synthesized from titanium isopropoxide, the corresponding lanthanide acetate and methacrylic acid. The type of cluster obtained strongly depends on the size of the lanthanide ion.