DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4 DCAF1 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billioncompound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning. This led to the discovery of a compound (Z1391232269) with an SPR K D of 11 μM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR K D of 38 nM and cellular target engagement with EC 50 of 10 μM as measured by cellular thermal shift assay (CETSA). OICR-8268 is an excellent tool compound to enable the development of next-generation DCAF1 ligands toward cancer therapeutics, further investigation of DCAF1 functions in cells, and the development of DCAF1-based PROTACs.

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ABSTRACT:In an effort to develop potent antithrombotic agents, a series of novel 2-aminobenzamide derivatives were synthesized and screened for their in vivo antithrombotic activity. Among the 23 compounds tested, compound (8g) showed the most promising antithrombotic activity, which was comparable with clinically used aspirin or warfarin, but at variance with these standard drugs, 8g did not exhibit the increased bleeding time, suggesting its potential as a novel antithrombotic agent.

Aim: A series of novel quinazolinone derivates was synthesized and assessed for their ability to inhibitory action on pancreatic lipase. The cyclization of quinazolinone-4(3H)-one derivatives was achieved, whereas carbon-carbon cross coupling reactions were carried out on cyclized quinazolinone-4(3H)-one. This synthesis method afforded corresponding 2, 3 and 6 substituted quinazolin-4(3H)-ones (3a to 3m) with moderate to high yields. Methods: Benzamide derivatives (1a-1b) were synthesized from anthranilic acid using acid-amine reaction, followed by cyclization using catalytic p-toluene sulfonic acid and oxidation using (diacetoxyiodo)benzene to give bromo substituted quinazolin-4(3H)-ones (2a-2b), which were cross coupled to suitable boronic acid using Suzuki-Miyaura condition to obtain desired compound (3a-3m). All synthesized compounds were characterized by FTIR, proton NMR, LC-MS analysis, checked for their drug likeness, absorption and evaluated for in vitro pancreatic lipase inhibition activity. Results: Analytical interpretation of all compounds with infrared, proton NMR and LC-MS spectroscopy confirmed their correct structure. All compounds (3a-3m) show good absorption and have reasonably good molecular properties except 3c and 3m which violate two criteria for Lipinski’s rule. Whereas, Compounds 3l and 3m showed IC50 value of 13.13±0.84 µg/mL and 13.80±1.27 µg/mL respectively comparable to the Orlistat (12.72±0.97µg/mL), a US FDA approved drug for the treatment of obesity. Conclusion: Pancreatic lipase is an important lipolytic enzyme, synthesized and secreted through pancreas, plays an important role in dietary trigycerol absorption and metabolism. Therefore, reducing fat absorption through pancreatic lipase inhibition is a promising strategy to treat obesity. Based upon our findings, compounds 3l and 3m can be further developed as potent anti-obesity agents.

Aim: Novel quinazolin-4(3H)-one heterocycles were synthesized and assessed for their anti-diabetic activity. Non-enzymatic glycosylation of haemoglobin assay was carried out to identify their potential as anti-diabetic. The cyclization of quinazolinone-4(3H)-one heterocycles was achieved, whereas carbon-carbon cross coupling reactions were carried out using Sonogashira and Suzuki-Miyaura reaction conditions and characterized with analysis. This synthesis method afforded corresponding 2, 3 and 6 substituted quinazolin-4(3H)-ones (3a to 3m) with excellent yields. Methods: 2-Amino-6-bromobenzoic acid was used as a substrate which was converted to corresponding benzamide derivatives (1a-1b)  by reaction with benzylamine or cyclohexylamine using acid-amine reaction, followed by cyclization and oxidation using suitable aldehyde in DMSO under microwave condition to give bromo substituted quinazolin-4(3H)-ones (2a-2c), which were cross coupled to suitable terminal alkyne with palladium catalyst as well as copper co-catalyst using Sonogashira condition to obtain desired (3a-3h) and suitable boronic acid with palladium catalyst using Suzuki-Miyaura condition to obtain desired (3i-3m). All synthesized compounds were characterized by FTIR, proton NMR, LC-MS analysis and evaluated for in vitro anti-diabetic activity using non-enzymatic glycosylation of haemoglobin assay. Results: Compounds 3m showed good inhibition of glycosylation of haemoglobin which in turn suggest good anti-oxidant potential on metabolism of glucose and hence lower glucose concentration. It showed IC50 value of 35.91±0.82 µg/mL which was comparable to the standard alpha tocopherol (34.47±0.87µg/mL). Conclusion: In-vitro non-enzymatic glycosylation of haemoglobin method is one of important assays to judge the control of diabetes. The haemoglobin present in RBCs has an affinity to bind with glucose. The greater the glucose level in blood, more amount of glucose-bound (called glycosylated) haemoglobin will be formed. Accordingly, presence of lower concentration of glycosylated haemoglobin is a sure guide to the lower concentration of glucose in the blood. Synthesized compounds (3a-3m) lower the blood glucose level and 3m has highest potential among those which can be further developed as potent anti-diabetic.