pH low insertion peptides conjugated to fatty acid metabolism inhibitors to prevent cancer cell proliferation

In this study, our objective was to develop pHLIP-fatty acid metabolism inhibitor conjugates to prevent cancer cell proliferation. Initially, we conjugated inhibitors to two pHLIPs, a reported and a designed sequence. Through intrinsic tryptophan fluorescence and circular dichroism measurements, we assessed the conjugates' potency to insert and structure in a pH-dependent manner into large unilamellar vesicles of different lipidic compositions. We observed variations in structuration and insertion based on the peptide sequence, cargo lipophilicity, and vesicle composition. Finally, we evaluated the ability of the conjugates to prevent tumor growth in 2D acidic cancer cells and 3D cancer cell models. Under DHA ferroptotic inducer conditions, the conjugates successfully inhibited cancer cell proliferation. Additionally, fluorescent variants of the conjugates stained the acidic compartments of tumor spheroids, indicating a pH preference for cells with extracellular acidification.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 202

Targeting cancer cells in acidosis with conjugates between the carnitine palmitoyltransferase 1 inhibitor etomoxir and pH (low) insertion peptides

Targeting enzymes involved in tumor metabolism is a promising way to tackle cancer progression. The inhibition of carnitine palmitoyltransferase 1 (CPT1) by etomoxir (Eto) efficiently slows down the growth of various cancers. Unfortunately, the clinical use of this drug was abandoned because of hepatotoxic effects. We report the development of pH-sensitive peptide (pHLIP)-drug conjugate to deliver Eto selectively to cancer cells exposed to acidic microenvironmental conditions. A newly designed sequence for the pHLIP peptide, named pHLIPd, was compared with a previously published reference pHLIP peptide, named pHLIPr. We showed that the conjugate between pHLIPd and Eto has a better pH-dependent insertion and structuration than the pHLIPr-based conjugate inside POPC vesicles. We observed antiproliferative effects when applied on acid-adapted cancer cells, reaching a larger inhibitory activity than Eto alone. In conclusion, this study brings the first evidence that pHLIP-based conjugates with a CPT1 inhibitor has the potential to specifically target the tumor acidic compartment and exert anticancer effects while sparing healthy tissues

Investigation of chalcogen bioisosteric replacement in a series of heterocyclic inhibitors of tryptophan 2,3-dioxygenase

Selenium is an underexplored element that can be used for bioisosteric replacement of lower molecular weight chalcogens such as oxygen and sulfur. More studies regarding the impact of selenium substitution in different chemical scaffolds are needed to fully grasp this element's potential. Herein, we decided to evaluate the impact of selenium incorporation in a series of tryptophan 2,3-dioxygenase (TDO2) inhibitors, a target of interest in cancer immunotherapy. First, we synthesized the different chalcogen isosteres through Suzuki-Miyaura type coupling. Next, we evaluated the isosteres' affinity and selectivity for TDO2, as well as their lipophilicity, microsomal stability and cellular toxicity on TDO2-expressing cell lines. Overall, chalcogen isosteric replacements did not disturb the on-target activity but allowed for a modulation of the compounds' lipophilicity, toxicity and stability profiles. The present work contributes to our understanding of oxygen/sulfur/selenium isostery towards increasing structural options in medicinal chemistry for the development of novel and distinctive drug candidates