Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader

Phosphatidylinositol 5-phosphate 4-kinase, type II, gamma (PIP4K2C) remains a poorly understood lipid kinase with minimal enzymatic activity but potential scaffolding roles in immune modulation and autophagy-dependent catabolism. Achieving potent and selective agents for PIP4K2C while sparing other lipid and non-lipid kinases has been challenging. Here, we report the discovery of the highly potent PIP4K2C binder TMX-4102, which shows exclusive binding selectivity for PIP4K2C. Furthermore, we elaborated the PIP4K2C binder into TMX-4153, a bivalent degrader capable of rapidly and selectively degrading endogenous PIP4K2C. Collectively, our work demonstrates that PIP4K2C is a tractable and degradable target, and that TMX-4102 and TMX-4153 are useful leads to further interrogate the biological roles and therapeutic potential of PIP4K2C.     

The cytotoxicity of trifluoromethyl boron derivatives and mode of action in human Tmolt3 T leukemic cells

Trifluoromethylboron derivatives proved to be cytotoxic in a number of murine and human leukemic and lymphoma screens. Solid tumor growth, e.g. glioma HS 683, breast Mck‐7 and colon adenocarcinoma SW480, was reduced significantly by the compounds. Human Tmolt₃ T‐cell leukemia DNA synthesis was inhibited preferentially by the derivatives, with marginal effects on RNA and protein syntheses, after 60 min at 100 µM . The agents appeared to act by multiple mechanisms in that they inhibited the activities of DNA polymerase α, dihydrofolate reductase and nucleosides, significantly within 60 min at 100 µM . Deoxyribonucleotide pools were reduced after 60 min incubation with the compounds. Tmolt₃ DNA fragmentation and reduced ct‐DNA viscosity were evident after 24 h of incubation at 100 µM . ct‐DNA thermal denaturation studies indicated that the agents caused some type of interaction with the bases of DNA. Copyright © 2000 John Wiley & Sons, Ltd.     

New insights on the thermal degradation pathways of neat poly(furfuryl alcohol) and poly(furfuryl alcohol)/SiO2 hybrid materials

Poly(furfuryl alcohol)/SiO₂ hybrid material was prepared and properties characterized in comparison with those of neat poly(furfuryl alcohol) (PFA) thermoset. A morphological study conducted by transmission electron microscopy (TEM) on the hybrid material reveals well-dispersed silica nanoclusters. Combination of micro- and submicro-structural organizations between the organic and inorganic networks generates new thermo-mechanical performances. A study of relaxation process by dynamic mechanical analysis (DMA) gives some evidence of the nanoconfinement effect on the hybrid network. These restrictions on the molecular mobility lead to an increase of thermal stability of the PFA/SiO₂ material compared to the unfilled matrix. Thermogravimetric analyses (TGAs) coupled with GC-MS have permitted us to highlight a multi-step degradation pathway and chain scission reactions are proposed based on identified VOCs.     

Four-membered ring cyclic ketene –O,O–, –O,S–, –O,N–, –S,S–, –S,N–, and –N,N–acetals and their corresponding cations: a computational study

A systematic computational study of four-membered cyclic ketene –O,O–, –O,S–, –O,N–, –S,N– and –N,N-acetals as well as their protonated analogs have been performed at the second order M?ller Plesset level with a polarized triple zeta basis set. The main purpose of this study was to make predictions about the nucleophilicity of these systems and the variations in nucleophilicity with the hetero atoms. Our calculations suggest that all six target molecules are good nucleophiles, and that the N,N analog is the strongest and the S,S analog the weakest nucleophile. Our results include molecular geometries, bond lengths, proton affinities, vibrational frequencies, and calculated charges.     

Eco-friendly composite resins based on renewable biomass resources: Polyfurfuryl alcohol/lignin thermosets

The properties of an innovative polyfurfuryl alcohol (PFA)/lignin combined matrix have been investigated. Furfuryl alcohol (FA) and lignin are, respectively, monomeric and polymeric precursors issued from biomass feedstock. In the present work, a plasticized lignin (PL) has been blended during polymerization of FA into PFA. Two kinds of samples were prepared at different FA/lignin ratio. Structural investigations were made on resins by ¹³C NMR while the thermo-mechanical performances of the combined materials were studied using thermogravimetric (TGA) and dynamic mechanical analysis (DMA). TGA results have permitted us to determine the thermal stability and the composition of the cured material on the basis of the ash content. According with these results, it was found that the lignin ratio in the cured material is more important than in the initial threshold. The TGA reveals that the PFA/PL thermo-oxidative degradation occurs at higher temperature compared to the natural (PL) component system, together with a lower rate of decomposition. This underlines a good interpenetration of lignin within the furanic matrix. The morphologies of the combined PFA/lignin systems, controlled by scanning electron microscopy (SEM), reveal a monophasic structure. These observations are in good agreement with the presence of a unique relaxation peak as shown in the DMA results.     

Mutant‐Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug‐Resistant Mutations

Targeting epidermal growth factor receptor (EGFR) through an allosteric mechanism provides a potential therapeutic strategy to overcome drug‐resistant EGFR mutations that emerge within the ATP binding site. Here, we develop an allosteric EGFR degrader, DDC‐01‐163, which can selectively inhibit the proliferation of L858R/T790M (L/T) mutant Ba/F3 cells while leaving wildtype EGFR Ba/F3 cells unaffected. DDC‐01‐163 is also effective against osimertinib‐resistant cells with L/T/C797S and L/T/L718Q EGFR mutations. When combined with an ATP‐site EGFR inhibitor, osimertinib, the anti‐proliferative activity of DDC‐01‐163 against L858R/T790M EGFR‐Ba/F3 cells is enhanced. Collectively, DDC‐01‐163 is a promising allosteric EGFR degrader with selective activity against various clinically relevant EGFR mutants as a single agent and when combined with an ATP‐site inhibitor. Our data suggests that targeted protein degradation is a promising drug development approach for mutant EGFR.     

A genome-wide overexpression screen in yeast for small-molecule target identification

We describe a multicopy gene suppression screen of drug sensitivity in Saccharomyces cerevisiae that facilitates the identification of cellular targets of small molecules. An array of yeast transformants harboring a multicopy yeast genomic library was screened for resistance to growth inhibitors. Comparison of array growth patterns for several such inhibitors allowed the differentiation of general and molecule-specific genetic suppressors. Specific resistance to phenylaminopyrimidine (1), an inhibitor identified from a kinase-directed library, was associated with the overexpression of Pkc1 and a subset of downstream kinases. Components of two other pathways (pheromone response/filamentous growth and Pho85 kinase) that genetically interact with the PKC1 MAPK signaling cascade were also identified. Consistent with the suppression screen, inhibitor 1 bound to Pkc1 in yeast cell lysate and inhibited its activity in vitro. These results demonstrate the utility of this approach for the rapid deconvolution of small-molecule targets.