Tunable Cysteine-Targeting Electrophilic Heteroaromatic Warheads Induce Ferroptosis

Abstract

Once considered potential liabilities, the modern era witnesses a renaissance of interest in covalent inhibitors in drug discovery. The available toolbox of electrophilic warheads is limited by constraints on tuning reactivity and selectivity. Following our work on a class of ferroptotic agents termed CETZOLEs, we discovered new tunable heterocyclic electrophiles which are capable of inducing ferroptosis. The biological evaluation demonstrated that thiazoles with an alkyne electrophile at the 2-position selectively induce ferroptosis with high potency. Density functional theory calculations and NMR kinetic studies demonstrated the ability of our heterocycles to undergo thiol addition, an apparent prerequisite for cytotoxicity. Chemoproteomic analysis indicated several potential targets, the most prominent among them being GPX4 protein. These results were further validated by western blot analysis and the cellular thermal shift assay. Incorporation of these heterocycles into appropriate pharmacophores generated highly cytotoxic agents such as the analogue BCP-T.A, with low nM IC50 values in ferroptosis-sensitive cell lines.

Facile and General Electrochemical Diselenylation of Terminal Alkynes

“…A lkynes are one of the most flexible building blocks and widely used as sustainable feedstocks for chemical synthesis, 1 as well as in the production of numerous medications and materials. 2,3 Catalytic difunctionalization of these π systems is a direct and efficient method to access a variety of structurally diverse trisubstituted compounds. 4−7 Trisubstituted alkenes are pivotal structural motifs in the structure of numerous medicines 8−10 and materials, 11 as well as helpful precursors for other functional groups and chiral centers.…”

“…Alkynes are one of the most flexible building blocks and widely used as sustainable feedstocks for chemical synthesis, as well as in the production of numerous medications and materials. , Catalytic difunctionalization of these π systems is a direct and efficient method to access a variety of structurally diverse trisubstituted compounds. − Trisubstituted alkenes are pivotal structural motifs in the structure of numerous medicines − and materials, as well as helpful precursors for other functional groups and chiral centers . The methods employed, however, rely heavily on the use of organometallic species and require high-temperature or multistep reactions (Scheme a). − More recently, radical-mediated reactions have been devised, which provide an effective technique for difunctionalizing terminal alkynes. − In general, a radical is generated from various radical precursors, such as sulfonyl chlorides, α,β-unsaturated ketones, activated alkyl bromides, fluoroalkyl iodides, etc., − which is via a single electron transfer (SET) process employing transition metal species, − photocatalysts, − or electrocatalysis (Scheme b).…”

First-in-Class Dual Mechanism Ferroptosis-HDAC Inhibitor Hybrids

“…This compound induces ferroptosis but has a simpler structure, making its incorporation into hybrid molecules easier. In addition, extensive SAR studies in our laboratory 52 reveal that the small 2-alkynyl thiazole system retains the ability to induce ferroptosis with wider group tolerance at the 5-position. We performed two different types of structural modifications; the first via a carboxylate at the 5position appropriate for amide coupling (Figure 2E), and the second via a formyl group at this position for Wittig reactions (Figure 2E).…”

Novel Covalent Probe Selectively Targeting Glutathione Peroxidase 4 In Vivo: Potential Applications in Pancreatic Cancer Therapy

“…Importantly, A16 exhibited greater potency than the existing GPX4 inhibitors, ML162 , and ML210 . Furthermore, negligible inhibitory activity was observed in the colon cancer cell line HCT116, which is known to be insensitive to ferroptosis (Figure C). , A16 demonstrated the ability to induce cell death in various types of cancer cells beyond pancreatic cancer (Tables S3 and S4 in SI_1), which is consistent with the behavior of ML162 and ML210 . This observation highlights the feasibility of utilizing ferroptosis as a pathway for suppressing different types of cancer cells.…”