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Hundreds of cytotoxic natural or synthetic lipidic compounds contain chiral alkynylcarbinol motifs, but the mechanism of action of those potential therapeutic agents remains unknown. Using a genetic screen in haploid human cells, we discovered that the enantiospecific cytotoxicity of numerous terminal alkynylcarbinols, including the highly cytotoxic dialkynylcarbinols, involves a bioactivation by HSD17B11, a short-chain dehydrogenase/reductase (SDR) known to oxidize the C-17 carbinol center of androstan-3-alpha,17-beta-diol to the corresponding ketone. A similar oxidation of dialkynylcarbinols generates dialkynylketones, that we characterize as highly protein-reactive electrophiles. We established that, once bioactivated in cells, the dialkynylcarbinols covalently modify several proteins involved in protein-quality control mechanisms, resulting in their lipoxidation on cysteines and lysines through Michael addition. For some proteins, this triggers their association to cellular membranes and results in endoplasmic reticulum stress, unfolded protein response activation, ubiquitin-proteasome system inhibition and cell death by apoptosis. Finally, as a proof-of-concept, we show that generic lipidic alkynylcarbinols can be devised to be bioactivated by other SDRs, including human RDH11 and HPGD/15-PGDH. Given that the SDR superfamily is one of the largest and most ubiquitous, this unique cytotoxic mechanism-of-action could be widely exploited to treat diseases, in particular cancer, through the design of tailored prodrugs., Competing Interests: PD, EJ, JM, PZ, CB, CN, JI, AR, KP, RH, Md, MM, RS, OB, OB, MO, VB, SH No competing interests declared, DL Dymytrii Listunov is one of the inventors on a patent deposited on related molecules, PR Pauline Rullière is one of the inventors on a patent deposited on related molecules, SB Stéphanie Ballereau is one of the inventors on a patent deposited on related molecules, VM Valérie Maraval is one of the inventors on a patent deposited on related molecules, PC Patrick Calsou is one of the inventors on a patent deposited on related molecules, YG Yves Génisson is one of the inventors on a patent deposited on related molecules, RC Remi Chauvin is one of the inventors on a patent deposited on related molecules, SB Sébastien Britton is one of the inventors on a patent deposited on related molecules, (© 2022, Demange et al.)

GAS41 is an emerging oncogene overexpressed and implicated in multiple cancers, including non-small cell lung cancer (NSCLC). GAS41 is a dimeric protein that contains the YEATS domain, which is involved in the recognition of lysine-acylated histones. Here, we report the development of GAS41 YEATS inhibitors by employing a fragment-based screening approach. These inhibitors bind to GAS41 YEATS domain in a channel constituting a recognition site for acylated lysine on histone proteins. To enhance inhibitory activity, we developed a dimeric analog with nanomolar activity that blocks interactions of GAS41 with acetylated histone H3. Our lead compound engages GAS41 in cells, blocks proliferation of NSCLC cells, and modulates expression of GAS41-dependent genes, validating on-target mechanism of action. This study demonstrates that disruption of GAS41 protein-protein interactions may represent an attractive approach to target lung cancer cells. This work exemplifies the use of bivalent inhibitors as a general strategy to block challenging protein-protein interactions., Competing Interests: Declaration of interests D.L., B.M.L., E.K., A.W., J.G., and T.C. are co-inventors on a patent application for GAS41 inhibitors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Extension of a structure-activity relationship study of the antitumor cytotoxicity of lipidic dialkynylcarbinols (DACs) is envisaged by formal methinylogation of one of the ethyndiyl moieties of the DAC warhead into the corresponding allenylalkynylcarbinol (AllAC) counterpart. External AllACs were directly obtained by methinylation of the parent DACs with formaldehyde in either the racemic or scalemic series. Isomers containing external progargyl and propynyl motifs were also prepared. Internal AllACs were obtained as racemic statistical mixtures of stereoisomers in two steps from the key C 5 -DAC rac-TIPS-C≡C-CH(OH)-C≡CH and aldehydes. Kinetic resolution of the (S)-C 5 -DAC in 97 % ee and (R)-C 5 -DAC in 99 % ee was achieved by sequential lipase-mediated acetylation/hydrolysis using the Candida antartica lipase (Novozyme 435). The four internal AllAC stereoisomers were prepared by asymmetric methinylation with (R)- or (S)-diphenylprolinol as chiral auxiliary. Cytotoxicity assays on HCT116 cancer cells showed that the most active (eutomeric) external or internal AllAC exhibits an S configuration, a fatty chain length of n=12, and a 50 % inhibitory concentration IC 50 ≈1.0 μm., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In line with a recent study of the pharmacological potential of bioinspired synthetic acetylenic lipids, after identification of the terminal dialkynylcarbinol (DAC) and butadiynyl alkynylcarbinol (BAC) moieties as functional antitumor pharmacophoric units, this work specifically addresses the issue of carbon backbone length. A systematic variation of the aliphatic chain length was thus carried out in both the DAC and BAC series. The critical impact of the length of the lipidic skeleton was first confirmed in the racemic series, with the highest cytotoxic activity observed for C 17 to C 18 backbones. Enantiomerically enriched samples were prepared by asymmetric synthesis of the optimal C 18 DAC and C 17 BAC derivatives. Samples with upgraded enantiomeric purity were alternatively produced by enzymatic kinetic resolution. Eutomers possessing the S configuration displayed cytotoxicity IC 50 values as low as 15 nm against HCT116 cancer cells, the highest level of activity reached to date in this series., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Chiral lipidic dialkynylcarbinols (DACs), recently highlighted as antitumoral pharmacophores, have been conjugated to difluoroboron-dipyrromethene (bodipy), 7-hydroxy-coumarine, and 7-nitro-benzoxadiazole (NBD) fluorophore motifs through triazole clips. The labeled lipids preserve cytotoxic activity against HCT116 cells, and fluorescence microscopy of the stained cells showed clear signals in the intra-cellular membrane system. While the bodipy conjugate also labels lipid droplets very brightly, as expected, the coumarine and NBD probes appear as promising specific tools for the identification of the intra-cellular targets of DACs' cytotoxicity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Illumination by acetylene: Systematic structural variations in a series of archetypal acetylenic lipids derived from the naturally occurring (S,E)-icos-4-en-1-yn-3-ol allowed the discovery of a series of 3R-like 1,4-di-unsaturated carbinol units with a significant and systematic enantiomeric effect on cytotoxicity., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)