Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy

Abstract

Receptor-interacting protein (RIP) kinase 1 is involved in immune-mediated inflammatory diseases including ulcerative colitis (UC) by regulating necroptosis and inflammation. Our group previously identified TAK-632 ( 5 ) as an effective necroptosis inhibitor by dual-targeting RIP1 and RIP3. In this study, using ligand-based substituent-anchoring design strategy, we focused on the benzothiazole ring to obtain a series of TAK-632 analogues showing significantly improving on the anti-necroptosis activity and RIP1 selectivity over RIP3. Among them, a conformational constrained fluorine-substituted derivative ( 25 ) exhibited 333-fold selectivity for RIP1 ( K d = 15 nmol/L) than RIP3 ( K d > 5000 nmol/L). This compound showed highly potent activity against cell necroptosis (EC 50 = 8 nmol/L) and systemic inflammatory response syndrome (SIRS) induced by TNF- α in vivo. Especially, it was able to exhibit remarkable anti-inflammatory treatment efficacy in a DSS-induced mouse model of UC. Taken together, the highly potent, selective, orally active anti-necroptosis inhibitor represents promising candidate for clinical treatment of UC.

Crystallography-Guided Optimizations of the Keap1–Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides

“…Water (10 mL) was added to the reaction mixture and diluted with ethyl acetate (50 mL) and washed with saturated brine (30 mL × 2). The organic layer was dried by Na 2 SO 4 , filtered, and the solvent was removed under reduced pressure . The crude residue was purified by flash column chromatography (DCM/MeOH = 20:1) on silica gel to afford the desired compound 4a (115 mg, 0.18 mmol, 79% yield) as a white solid.…”

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

“…Necroptosis inhibition TAK-632 Ponatinib RIP1 and RIP3 inhibitiors [440,445] (with TAK-632 also being a pan-RAF inhibitor [441]) Mitophagy inhibitors (helping downregulating drug resistance in certain tumors) [444] Ketaconazole Sorafenib Mito-CP and Mito-Metformin Mitophagy inducers (leading to apoptosis due to insufficient number of mitochondria) [444] Abbreviations: ETC: electron transport chain, IDH: isocitrate dehydrogenase, KGDH: α-ketoglutarate dehydrogenase, mtDNA: mitochondrial DNA, PDH: pyruvate dehydrogenase, ROS: reactive oxygen species, TCA: tricarboxylic acid cycle.…”

“…Inhibition of mtDNA translation and transcription [7,[29][30][31], along with apoptosis [41,[43][44][45]439] and necroptosis [440,441] induction are promising anti-cancer therapies (Figure 2 and Table 3), discussed in more details in Sections 2.2 and 2.3.…”

Improving Druggability of Novel Diarylpyrimidine NNRTIs by a Fragment-Based Replacement Strategy: From Biphenyl-DAPYs to Heteroaromatic-Biphenyl-DAPYs

“…Male Sprague–Dawley rats (180–230 g) were randomly divided into groups ( n = 3) to receive the low dosage level (5 mg·kg –1 ) or the medium dosage level (10 mg·kg –1 ) of the compound . The sample was suspended in a mixture of S18 DMSO, poly­(ethylene glycol) (PEG) 400, and normal saline (10/40/50, V/V) before the experiment.…”