Targeting Tropomyosin Receptor Kinase in Cutaneous CYLD Defective Tumors With Pegcantratinib: The TRAC Randomized Clinical Trial.

Importance: There are no medical interventions for the orphan disease CYLD cutaneous syndrome (CCS). Transcriptomic profiling of CCS skin tumors previously highlighted tropomyosin receptor kinases (TRKs) as candidate therapeutic targets.

Objective: To investigate if topical targeting of TRK with an existing topical TRK inhibitor, pegcantratinib, 0.

Development and validation of LC-MS/MS with in-source collision-induced dissociation for the quantification of pegcantratinib in human skin tumors.

Aim: Pegcantratinib is a mini-PEGylated K252a derivative, under clinical evaluation as an anticancer agent acting through inhibition of the tropomyosin receptor kinase. A method for quantifying pegcantratinib in skin tumor biopsies of patients was required to determine tumor drug penetration.

Methods & Results: A sensitive and PEGylated molecule specific HPLC-MS/MS method coupled with in-source collision-induced dissociation was developed.

Novel RasGRF1-derived Tat-fused peptides inhibiting Ras-dependent proliferation and migration in mouse and human cancer cells.

Mutations of RAS genes are critical events in the pathogenesis of different human tumors and Ras proteins represent a major clinical target for the development of specific inhibitors to use as anticancer agents. Here we present RasGRF1-derived peptides displaying both in vitro and in vivo Ras inhibitory properties. These peptides were designed on the basis of the down-sizing of dominant negative full-length RasGRF1 mutants.

NMR structure of two novel polyethylene glycol conjugates of the human growth hormone-releasing factor, hGRF(1-29)-NH2.

Two novel mono-PEGylated derivatives of hGRF(1-29)-NH(2) [human growth hormone-releasing factor, fragment 1-29] have been synthesized by regio-specific conjugation of Lys(12) or Lys(21) to a monomethoxy-PEG(5000) chain (compounds Lys(12)PEG-GRF and Lys(21)PEG-GRF). The PEG moiety has been covalently linked at the amino group of a norleucine residue via a carbamate bond. The Lys(12)PEG-GRF regioisomer was found to be slightly less active in vitro than both the unmodified peptide and Lys(21)PEG-GRF.

NMR conformational analysis of antide, a potent antagonist of the gonadotropin releasing hormone.

Antide is a decapeptide [(N-Ac-D-Nal(1)-D-Cpa(2)-D-Pal(3)-Ser(4)-Lys(Nic)(5)-D-Lys(Nic)(6)-Leu(7)-Ilys(8)-Pro(9)-D-Ala(10)-NH(2)] that acts in vivo as an antagonist of GnRH (gonadotropin-releasing hormone). The conformational behavior of antide has been studied in water, TFE, DMF, and DMSO solutions by means of 2D-NMR spectroscopy and molecular dynamics calculations. Antide adopts in aqueous solution a delta-shaped backbone conformation, which is characterized by an irregular turn around residues D-Pal(3)-Ser(4) and by the close spatial proximity of the side chains belonging to D-Nal(1) and Ilys(8) (as many as 17 NOE peaks were detected between these side chains).