FV-162 is a novel, orally bioavailable, irreversible proteasome inhibitor with improved pharmacokinetics displaying preclinical efficacy with continuous daily dosing.

Approved proteasome inhibitors have advanced the treatment of multiple myeloma but are associated with serious toxicities, poor pharmacokinetics, and most with the inconvenience of intravenous administration. We therefore sought to identify novel orally bioavailable proteasome inhibitors with a continuous daily dosing schedule and improved therapeutic window using a unique drug discovery platform. We employed a fluorine-based medicinal chemistry technology to synthesize 14 novel analogs of epoxyketone-based proteasome inhibitors and screened them for their stability, ability to inhibit the chymotrypsin-like proteasome, and antimyeloma activity in vitro. The tolerability, pharmacokinetics, pharmacodynamic activity, and antimyeloma efficacy of our lead candidate were examined in NOD/SCID mice. We identified a tripeptide epoxyketone, FV-162, as a metabolically stable, potent proteasome inhibitor cytotoxic to human myeloma cell lines and primary myeloma cells. FV-162 had limited toxicity and was well tolerated on a continuous daily dosing schedule. Compared with the benchmark oral irreversible proteasome inhibitor, ONX-0192, FV-162 had a lower peak plasma concentration and longer half-life, resulting in a larger area under the curve (AUC). Oral FV-162 treatment induced rapid, irreversible inhibition of chymotrypsin-like proteasome activity in murine red blood cells and inhibited tumor growth in a myeloma xenograft model. Our data suggest that oral FV-162 with continuous daily dosing schedule displays a favorable safety, efficacy, and pharmacokinetic profile in vivo, identifying it as a promising lead for clinical evaluation in myeloma therapy.

[Dramatic efficacy of chemotherapy with 5-fluorouracil and dacarbazine in a patient with metastatic glucagonoma and cardiac insufficiency]. / Efficacité spectaculaire d'une chimiothérapie par 5-fluoro-uracile et dacarbazine chez un malade atteint de glucagonome métastatique avec insuffisance cardiaque.

Malignant glucagonoma is an exceptional pancreatic endocrine tumour, with frequent dermatologic symptoms, diabetes and degradation of the general health status. Prognosis is unfavourable when liver metastases are present due to the usual inefficiency of chemotherapy. We report here an observation of a patient who was treated for a glucagonoma with multiple liver metastases, migratory necrolytic erythema, dilated cardiomypathy and diabetes that dramatically improved after a dacarbazin-based chemotherapy, allowing subsequent surgical resection of the primary. The patient was still alive and asymptomatic without progressive disease nearly two years after surgery.

Peptides enhance magnesium signature in calcite: insights into origins of vital effects.

Studies relating the magnesium (Mg) content of calcified skeletons to temperature often report unexplained deviations from the signature expected for inorganically grown calcite. These "vital effects" are believed to have biological origins, but mechanistic bases for measured offsets remain unclear. We show that a simple hydrophilic peptide, with the same carboxyl-rich character as that of macromolecules isolated from sites of calcification, increases calcite Mg content by up to 3 mole percent. Comparisons to previous studies correlating Mg content of carbonate minerals with temperature show that the Mg enhancement due to peptides results in offsets equivalent to 7 degrees to 14 degrees C. The insights also provide a physical basis for anecdotal evidence that organic chemistry modulates the mineralization of inorganic carbonates and suggest an approach to tuning impurity levels in controlled materials synthesis.

Role of molecular charge and hydrophilicity in regulating the kinetics of crystal growth.

The composition of biologic molecules isolated from biominerals suggests that control of mineral growth is linked to biochemical features. Here, we define a systematic relationship between the ability of biomolecules in solution to promote the growth of calcite (CaCO3) and their net negative molecular charge and hydrophilicity. The degree of enhancement depends on peptide composition, but not on peptide sequence. Data analysis shows that this rate enhancement arises from an increase in the kinetic coefficient. We interpret the mechanism of growth enhancement to be a catalytic process whereby biomolecules reduce the magnitude of the diffusive barrier, Ek, by perturbations that displace water molecules. The result is a decrease in the energy barrier for attachment of solutes to the solid phase. This previously unrecognized relationship also rationalizes recently reported data showing acceleration of calcite growth rates over rates measured in the pure system by nanomolar levels of abalone nacre proteins. These findings show that the growth-modifying properties of small model peptides may be scaled up to analyze mineralization processes that are mediated by more complex proteins. We suggest that enhancement of calcite growth may now be estimated a priori from the composition of peptide sequences and the calculated values of hydrophilicity and net molecular charge. This insight may contribute to an improved understanding of diverse systems of biomineralization and design of new synthetic growth modulators.

Inhibition of [14C]aminopyrine uptake in rat isolated gastric mucosal cells by two classes of psychotropic agents.

Certain CNS-active compounds decrease gastric acid secretion in vivo. In this study a number of tricyclic antipsychotic or antidepressant compounds together with haloperidol, a nontricyclic antipsychotic agent, were shown to inhibit dibutyryl-cAMP-stimulated [14C]aminopyrine uptake, an index of acid secretory activity in a rat isolated gastric mucosal cell preparation. The observed order of potency was: thioridazine greater than chlorpromazine greater than haloperidol approximately equal to desipramine approximately equal to imipramine greater than clozapine. Comparison of these potencies with those of the known (H+ + K+)ATPase inhibitors timoprazole and omeprazole revealed that the potency of timoprazole was similar to the one of clozapine while omeprazole was intermediate between thioridazine and chlorpromazine. Pirenzepine was ineffective.