Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAFV600E Protein

BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAF^V600E mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of BRAF^V600E has been proposed as an alternative strategy to avoid the onset of resistance. In this study, we designed a series of compounds where the BRAF kinase inhibitor encorafenib was conjugated to pomalidomide through different linkers. The synthesized compounds maintained their ability to inhibit the kinase activity of mutated BRAF with IC₅₀ values in the 40–88 nM range. Selected compounds inhibited BRAF^V600E signaling and cellular proliferation of A375 and Colo205 tumor cell lines. Compounds 10 and 11, the most active of the series, were not able to induce degradation of mutated BRAF. Docking and molecular dynamic studies, conducted in comparison with the efficient BRAF degrader P5B, suggest that a different orientation of the linker bearing the pomalidomide substructure, together with a decreased mobility of the solvent-exposed part of the conjugates, could explain this behavior.     

Performance evaluation of shared and separate inverted files

In this paper, two different structures for inverted files are analyzed and compared, when the relational join operation is taken into account. The structures are called shared and separate inverted files. The results are given of some experiments which show that the shared inverted organization is always advantageous when the inverted files are not sorted and is almost always advantageous when the files are sorted.     

On a Class of Elliptic-Parabolic Equations on Unbounded Intervals

We study a class of degenerate elliptic second order differential operators acting on some polynomial weighted function spaces on [0,+[. We show that these operators are the generators of C ₀-semigroups of positive operators which, in turn, are the transition semigroups associated with right-continuous normal Markov processes with state space [0,+]. Approximation and qualitative properties of both the semigroups and the Markov processes are investigated as well. Most of the results of the paper depend on a representation of the semigroups we give in terms of powers of particular positive operators of discrete type we introduced and studied in a previous paper.     

Failure of n‐uniqueness: a family of examples

In this paper, the connections between model theory and the theory of infinite permutation groups (see 11 ) are used to study the n‐existence and the n‐uniqueness for n‐amalgamation problems of stable theories. We show that, for any n ? 2, there exists a stable theory having (k + 1)‐existence and k‐uniqueness, for every k ? n, but has neither (n + 2)‐existence nor (n + 1)‐uniqueness. In particular, this generalizes the example, for n = 2, due to Hrushovski given in 3 . © 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim     

Equazioni monodimensionali di un gas viscoso barotropico con una perturbazione poco regolare

The equations for a barotropic viscous gas in one space dimensiondν=(μ(?ν_ε)_ε?p _ε)dt+dG,? _t +?²ν_ε=0,p=?^γ with a perturbationdG are considered under the assumption thatG is only a function of bounded variation inL ²(Θ) orH ₀ ¹ (Θ) (Θ=]0, α[) and the esistence and the uniqueness of the global solution in a class of solutions of «strong type» as well as in a class of solutions of «weak type» are proved. This result constitutes a generalization of the result of Kazhikhov [8] and that of Shelukhin [10] and contains preliminary considerations for the corrisponding stochastic equations.     

Wavelength-dependent electron and energy transfer pathways in a side-to-face ruthenium porphyrin/perylene bisimide assembly

A new side-to-face supramolecular array of chromophores, where a pyridyl-substituted perylene bisimide dye axially binds to two ruthenium porphyrin fragments, has been prepared by self-assembly. The array is formulated as DPyPBI[Ru(TPP)(CO)](2), where DPyPBI = N,N'-di(4-pyridyl)-1,6,7,12-tetra(4-tert-butylphenoxy)perylene-3,4:9,10-tetracarboxylic acid bisimide and TPP = 5,10,15,20-tetraphenylporphyrin. The photophysical behavior of DPyPBI[Ru(TPP)(CO)](2) has been studied by fast (nanoseconds) and ultrafast (femtoseconds) time-resolved techniques. The observed behavior sharply changes with excitation wavelength, depending on whether the DPyPBI or Ru(TPP)(CO) units are excited. After DPyPBI excitation, the strong fluorescence typical of this unit is completely quenched, and time-resolved spectroscopy reveals the occurrence of photoinduced electron transfer from the ruthenium porphyrin to the perylene bisimide dye (tau = 5.6 ps) followed by charge recombination (tau = 270 ps). Upon excitation of the Ru(TPP)(CO) fragments, on the other hand, ultrafast (tau < 1 ps) intersystem crossing is followed by triplet energy transfer from the ruthenium porphyrin to the perylene bisimide dye (tau = 720 ps). The perylene-based triplet state decays to the ground state on a longer time scale (tau = 9.8 micros). The photophysics of this supramolecular array provides remarkable examples of (i) wavelength-dependent behavior (a small change in excitation wavelength causes a sharp switch from electron to energy transfer) and (ii) intramolecular sensitization (the triplet state of the perylene bisimide, inaccessible in the free dye, is efficiently populated in the array).