A Small Molecule Pan-Inhibitor of Ras-Superfamily GTPases with High Efficacy Towards Rab7

Low molecular weight guanine triphosphate hydrolases (GTPases) are GTP-binding enzymes that play pivotal roles in cell biology. Grouped into three subfamilies which are designated by function, Ras, Rho and Rab GTPases are involved in signal transduction, cytoskeleton modulation, and macromolecule cargo transport and degradation, respectively. Mutation and aberrant gene expression levels have been linked to human diseases including cancer, immunodeficiencies, and neurological disorders. A high through-put screen of the Molecular Libraries Small Molecule Repository (MLSMR) identified a compound, ML282, which potently inhibits GTPases from all three subfamilies. Importantly, this represents the discovery of the first reported compound to inhibit Rab GTPases, especially Rab7, the mutation of which is a causal factor in a heritable neuropathy called Charcot-Marie-Tooth Type 2B disease. ML282 inhibits Rab7 with an average EC50 = 53.2 ± 0.35 nM and with high response, as compared to other GTPases in the panel. The subsequent structure activity relationships (SAR) and secondary assays demonstrate its use as a molecular probe for both biochemical and cellular studies

Drug repurposing from an academic perspective

Academia and small business research units are poised to play an increasing role in drug discovery, with drug repurposing as one of the major areas of activity. Here we summarize project status for a number of drugs or classes of drugs: raltegravir, cyclobenzaprine, benzbromarone, mometasone furoate, astemizole, R-naproxen, ketorolac, tolfenamic acid, phenothiazines, methylergonovine maleate and beta-adrenergic receptor drugs, respectively. Based on this multi-year, multi-project experience we discuss strengths and weaknesses of academic-based drug repurposing research. Translational, target and disease foci are strategic advantages fostered by close proximity and frequent interactions between basic and clinical scientists, which often result in discovering new modes of action for approved drugs. On the other hand, lack of integration with pharmaceutical sciences and toxicology, lack of appropriate intellectual coverage and issues related to dosing and safety may lead to significant drawbacks. The development of a more streamlined regulatory process world-wide, and the development of pre-competitive knowledge transfer systems such as a global healthcare database focused on regulatory and scientific information for drugs world-wide, are among the ideas proposed to improve the process of academic drug discovery and repurposing, and to overcome the “valley of death” by bridging basic to clinical sciences

Nephrocalcinosis and urolithiasis in children

The incidence of adult urolithiasis has increased significantly in industrialized countries over the past decades. Sound incidence rates are not available for children, nor are they known for nephrocalcinosis, which can appear as a single entity or together with urolithiasis. In contrast to the adult kidney stone patient, where environmental factors are the main cause, genetic and/or metabolic disorders are the main reason for childhood nephrocalcinosis and urolithiasis. While hypercalciuria is considered to be the most frequent risk factor, several other metabolic disorders such as hypocitraturia or hyperoxaluria, as well as a variety of renal tubular diseases, e. g., Dent's disease or renal tubular acidosis, have to be ruled out by urine and/or blood analysis. Associated symptoms such as growth retardation, intestinal absorption, or bone demineralization should be evaluated for diagnostic and therapeutic purposes. Preterm infants are a special risk population with a high incidence of nephrocalcinosis arising from immature kidney, medication, and hypocitraturia. In children, concise evaluation will reveal an underlying pathomechanism in > 75% of patients. Early treatment reducing urinary saturation of the soluble by increasing fluid intake and by providing crystallization inhibitors, as well as disease-specific medication, are mandatory to prevent recurrent kidney stones and/or progressive nephrocalcinosis, and consequently deterioration of renal function