Good ADME Properties Research Articles

Lagerstroemin from Lagerstroemia speciosa as Antibreast Cancer Candidate Targeting AURKA, EGFR and SRC Protein: A Comprehensive Computational Study

Breast cancer is a type of cancer that has a high rate of diagnosis and mortality in the world. Lagerestroemia speciosa is a herb that has anticancer activity. This study aims to analyze the compounds in L. speciosa that most act as anticancer of the breast. The compounds in L. speciosa were selected based on drug-likeness, physicochemical properties, ability to penetrate the lipid bilayer and toxicity. The Lagerstroemin target related to Lagestroemin breast cancer was predicted using DisGeNET, SWISS Target Prediction and cBioportal. Molecular docking between Lagerstroemin and AURKA, EGFR and SRC was performed using AutoDock Vina. The interaction stability of each complex was analyzed by molecular dynamic simulation using YASARA with parameters of RMSD protein, RMSD ligand, number of hydrogen bonds and molecular dynamic binding energy. Of the 22 compounds, Quercetin, Caffeic acid, Lagerstroemin and Dypirone were predicted to have good ADME properties and can easily penetrate lipid membranes. Therefore, Quercetin, Caffeic acid and Lagerstroemin were predicted to have anti-breast cancer bioactivity. Of the 3 compounds, Lagerstroemin had the lowest toxicity. Lagerstroemin was predicted to interact with breast cancer-related proteins AURKA, EGFR and SRC. Molecular docking and dynamics showed that Lagerestroemin interacted stably at the ATP binding site of the 3 proteins, so it was very potential as an inhibitor of these 3 proteins. Therefore, Lagerstroemin was predicted to be the compound in L. speciosa with the most potential breast anticancer agent by targeting AURKA, EGFR and SRC. HIGHLIGHTS Quercetin, Caffeic acid and Lagerstroemin from Lagerstroemia speciosa show promising anticancer properties for breast cancer treatment. Lagerstroemin stands out with low toxicity and potent anticancer activity, suggesting its safety and effectiveness as a therapeutic agent. Lagerstroemin interacts stably with breast cancer-related proteins AURKA, EGFR and SRC, indicating its potential as a powerful inhibitor targeting key pathways in breast cancer. GRAPHICAL ABSTRACT

Successful Identification of Key Phytoconstituents of Emblica officinalis as Potential Multitargeting Anti-Inflammatory and Antifungal Agents

Abstract: Introduction: Fungal infections are growing more rapidly and becoming a public health concern worldwide. The use of herbal medicines is now increasing due to their many functional properties with fewer side effects. Emblica officinalis, an important medicinal plant, exhibits many therapeutic properties. Method: In this article, the active phytoconstituents of Emblica officinalis were explored for their multitargeting activity as anti-inflammatory and antifungal by computational analysis. Results: A total of nine phytoconstituents including 3,6-di-Ogalloyl- D-glucose, Mucic acid-1,4-lactone-2-O-gallate, Mucic acid-1,4-lactone-5-O-gallate, Mucic acid-1,4-lactone-3-O-gallate, Mucic acid-1,4-lactone-3,5-di-O-gallate, 2,6-dimethoxy-4- (2-hydroxyethyl)phenol-1-O-beta-D-glucopyranoside, Apigenin-7-O-(6'-butyryl-beta-glucopyranoside), S-eriodictoyl-7-O-(6'-O-trans-p-coumaryl)-beta-D-glucopyranoside, and 1,2,3,4,6- penta-O-galloyl glucose showed better results as compared to standard drugs taken in the study. Conclusion: Further, these constituents indicated good ADME properties during the SwissADME online analysis.

Abstract LB268: Discovery of a potent, selective and brain penetrating PARP1 inhibitor, XZP-7797

Abstract First-generation PARP1/2 inhibitors are approved for the treatment of cancers, such as ovarian, prostate, pancreas, and breast cancers, with maximal activity against tumors harboring BRCA1/2 mutation or homologous recombination deficiency (HRD). However, PARP1/2 inhibitors in clinical use have severe hematological toxicities due to the inhibition of PARP2, which has been shown to play an important role in the survival of hematopoietic progenitor cells. Furthermore, the current data indicate that synthetic lethality with BRCA mutations is primarily caused by PARP1 inhibition and trapping, whereas PARP2 inhibition and trapping are not critical for anticancer activity. Therefore, the development of selective PARP1 inhibitors is expected to reduce the hematological adverse effects associated with PARP2 inhibition while maintaining the required efficacy. XZP-7797 is a potent, selective, and brain-penetrating PARP1 inhibitor with trapping ability. In biochemical assays, XZP-7797 is more than 1000-fold selective for PARP1 over PARP2 and other members of the PARP family, including PARP3, PARP5a, PARP5b, and PARP6. XZP-7797 can significantly inhibit MDA-MB-436 cell proliferation in vitro (IC50=2.4nM). In MDA-MB-436 tumor cells, XZP-7797 inhibits PARylation and increases γH2AX level in a concentration-dependent manner. XZP-7797 demonstrates rapid tumor regression in a dose-dependent manner in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. In a pancreatic cancer xenograft model, XZP-7797 can also significantly inhibit tumor growth. To evaluate the ability of XZP-7797 to cross the blood-brain barrier, an intracranial xenograft model of breast cancer is used. The results show that XZP-7797 can significantly inhibit the growth of intracranial tumors in mice at a dose of 10 mg/kg, demonstrating the brain-penetrating ability of XZP-7797. Additionally, XZP-7797 has great PK profiles in preclinical species after oral dosing and good ADME properties. In a 14-day toxicology study of XZP-7797 in SD Rats, XZP-7797 has no hematological adverse effects at the exposure that is 10 times higher than the exposure required to achieve superior efficacy. Citation Format: Yeqing Gao, Yuqian Lu, Bo Chen, Benke Jiang, Feng Wang, Genyan Zhang, Xifeng Ma, Dapeng Zhou, Chunmin Shi, Yunling Wang, Zhipeng Liu, Jun Sun, Huimin Zhou, Mei Xu, Jiakui Li, Bin Liu. Discovery of a potent, selective and brain penetrating PARP1 inhibitor, XZP-7797 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB268.

Molecular docking, characterization, ADME/toxicity prediction, and anti-ulcer activity of new quercetin derivatives on indomethacin-induced gastric ulcer in mice

Gastric ulcer (GU) is a serious upper gastrointestinal tract disorder that affects people worldwide. The drugs now available for GU treatment have a high rate of relapses and drug interactions, as well as mild to severe side effects. As a result, new natural therapeutic medications for treating GU with fewer negative side effects are desperately needed. Because of quercetin's (QCT) diverse pharmacological effects and unique structural features, we decided to semi-synthesize new QCT derivatives and test them for antiulcer activity. Docking assays were performed on the synthesized compounds to determine their affinity for TLR-4/MD-2, MyD88/TIR, and NF-κB domains, an important inflammatory pathway involved in GU development and progression. Mice were given oral famotidine (40 mg/kg/day), QCT, QCT pentamethyl (QPM), or QCT pentaacetyl (QPA) (50 mg/kg/day) for 5 days before GU induction by a single intraperitoneal injection of indomethacin (INDO; 18 mg/kg). QPM and QPA have a stronger binding affinity for TLR-4/MD-2, MyD88/TIR and NF-κB domains than QCT. In comparison, they demonstrated the greatest reduction in ulcer score and index, gastric MDA and nitric oxide (NO) contents, MyD88 and NF-κB expressions, and gastric TLR-4 immunostaining. They also enhanced the levels of GSH, CAT, COX-1, and COX-2 in the gastric mucosa, as well as HO-1 and Nrf2 expression, with histological regression in gastric mucosal lesions, with QPA-treated mice demonstrating the best GU healing. QPA is safe against all of the target organs and adverse pathways studied, with good ADME properties. However, further in vitro experiments are necessary to demonstrate the inhibitory effects of QPM and QPA on the protein targets of interest. In addition, preclinical research on its bioavailability and safety is essential before clinical management can be undertaken. Overall, the new QPA derivative could one day serve as the basis for a new class of potential antiulcer drugs.

Garlic as an effective antifungal inhibitor: A combination of reverse docking, molecular dynamics simulation, ADMET screening, DFT, and retrosynthesis studies

Fungal infections profoundly affect human health, causing a substantial number of infections and millions of fatalities annually on a global scale. The identification of new drugs targeting this infection is a challenge that is not yet complete. Natural products, including medicinal and aromatic plants, substances that act as sources of beneficial chemical compounds for the development of efficient therapies, are among the medicines that can be used to combat this type of infection. In this study, seven bioactive molecules derived from garlic plant as potential antifungal inhibitors were investigated using computational methods. Alliin and S-allyl-cysteine, bioactive molecules generated from garlic, showed good stability at the active site of the studied receptor (PDB code: 5TZ1). They provided binding energies of −4.80 and −4.90 Kcal/mol, and inhibition constant (Ki) values of 303.78 and 253.68 µM, respectively. Similarly, alliin and S-allyl-cysteine were stabilized in the active site of the target receptor by conventional hydrogen bonds with residues Ser507 (2.47 Å), Ser378 (3.01 Å), Met508 (2.62 Å, 3.46 Å), and His377 (3.00 Å), Ser378 (3.09 Å), Met508 (2.01 Å), Ser507 (2.26 Å), respectively. These results were confirmed by molecular dynamic simulation. The selected molecules comply with the most important drug rules such as Lipinski, Veber and Egan, have good ADME properties and are not toxic; therefore, these bioactive molecules have good pharmacokinetic properties and bioavailability. The retrosynthesis method has created a pathway for the synthesis of these candidate inhibitors. As a result, the outcomes of this study strongly suggest that Alliin, S-allyl-cysteine, are potential antifungal inhibitors in the future.

In silico prediction and in vitro assessment of novel heterocyclics with antimalarial activity

The development of new antimalarials is paramount to keep the goals on reduction of malaria cases in endemic regions. The search for quality hits has been challenging as many inhibitory molecules may not progress to the next development stage. The aim of this work was to screen an in-house library of heterocyclic compounds (HCUV) for antimalarial activity combining computational predictions and phenotypic techniques to find quality hits. The physicochemical determinants, pharmacokinetic properties (ADME), and drug-likeness of HCUV were evaluated in silico, and compounds were selected for structure-based virtual screening and in vitro analysis. Seven Plasmodium target proteins were selected from the DrugBank Database, and ligands and receptors were processed using UCSF Chimera and Open Babel before being subjected to docking using Autodock Vina and Autodock 4. Growth inhibition of P. falciparum (3D7) cultures was tested by SYBR Green assays, and toxicity was assessed using hemolytic activity tests and the Galleria mellonella in vivo model. From a total of 792 compounds, 341 with good ADME properties, drug-likeness, and no interference structures were subjected to in vitro analysis. Eight compounds showed IC50 ranging from 0.175 to 0.990 µM, and active compounds included pyridyl-diaminopyrimido-diazepines, pyridyl-N-acetyl- and pyridyl-N-phenyl-pyrazoline derivatives. The most potent compound (UV802, IC50 0.178 µM) showed no toxicophoric and was predicted to interact with P. falciparum 1-cysperoxidredoxin (PfPrx1). For the remaining 7 hits (IC50 < 1 μM), 3 showed in silico binding to PfPrx1, one was predicted to bind the haloacid dehalogenase-like hydrolase and plasmepsin II, and one interacted with the plasmodial heat shock protein 90.

Multitargeted C9-substituted ester and ether derivatives of berberrubine for Alzheimer's disease: Design, synthesis, biological evaluation, metabolic stability, and pharmacokinetics.

Berberrubine is a naturally occurring isoquinoline alkaloid and a bioactive metabolite of berberine. Berberine exhibits a wide range of pharmacological activities, including cholinesterase inhibition. The cholinesterase inhibitors provide symptomatic treatment for Alzheimer's disease; however, multitarget-directed ligands have the potential as disease-modifying therapeutics. Herein, we prepared a series of C9-substituted berberrubine derivatives intending to discover dual cholinesterase and beta-site amyloid-precursor protein cleaving enzyme 1 (BACE-1) inhibitors. Most synthesized derivatives possessed balanced dual inhibition (AChE and BChE) activity in the submicromolar range and a moderate inhibition against BACE-1. Two most active ester derivatives, 12a and 11d, display inhibition of AChE, BChE, and BACE-1. The 3-methoxybenzoyl ester derivative, 12a, inhibits electric eel acetylcholinesterase (EeAChE), equine serum butyrylcholinesterase (eqBChE), and human hBACE-1 with IC50 values of 0.5, 4.3, and 11.9 μM, respectively and excellent BBB permeability (Pe = 8 × 10-6 cm/s). The ester derivative 12a is metabolically unstable; however, its ether analog 13 is stable in HLM and exhibits inhibition of AChE, BChE, and BACE-1 with IC50 values of 0.44, 3.8, and 17.9 μM, respectively. The ether analog also inhibits self-aggregation of Aβ and crosses BBB (Pe = 7.3 × 10-6 cm/s). Administration of 13 at 5 mg/kg (iv) in Wistar rats showed excellent plasma exposure with AUC0-∞ of 28,834 ng min/ml. In conclusion, the multitargeted berberrubine ether derivative 13 is CNS permeable and has good ADME properties.

Discovery and Preclinical Study of Novel BTK Degrader HZ-Q1060

Introduction: Bruton's tyrosine kinase （BTK） is a clinical validated drug target for therapy of B cell lymphoma and autoimmune diseases. However, same as other kinase inhibitors, acquired drug resistance, which is the result of BTK C481S mutation, has been observed in patients. So reversible BTK inhibitors were developed to overcome acquired drug resistance of covalent BTK inhibitor. While, in order to have enough efficacy, reversible BTK inhibitors required much higher drug exposure which may lead to higher risk of adverse effect. Hence, it is urgent to develop new technique to overcome drug resistance caused by BTK C481S mutation. Proteolysis-targeting chimeras(PROTAC) is promising new strategy for drug development. PROTAC can achieve sustained target degradation in a catalytical mechanism. So comparing with traditional small molecule inhibitor, PROTAC drug has great advantage in solving acquired drug resistance. Therefore, with the aim of solving acquired drug resistance of 1st generation of BTK inhibitor, we identified a novel BTK-PROTAC HZ-Q1060 based on our in-house DaTProD® platform which is setting up to promote PROTAC development. After a series of evaluations, HZ-Q1060 has been validated as a promising pre-clinical candidate for further clinical development. Results:HZ-Q1060 can effectively degrade BTK in cancer cell lines and human PBMC, and the half degradation concentration (DC50) in Mino is less than 0.5nM. At the same time, HZ-Q1060 can also induce the degradation of intracellular mutant BTK-C481S protein.HZ-Q1060 has not observed any inhibition and degradation effect on other kinases except BTK, especially kinases that may be related to potential side effects by inhibiting, such as EGFR and TEC.In vitro cancer cell growth inhibition assay, it completely suppressed the cell proliferation of a panel of lymphoma cell lines such as Mino(IC50=0.11nM) and OCI-ly10(IC50=0.28nM).In the PK/PD experiment in mice, a single oral administration of medium dose can degrade more than 80% of BTK within 6 hours, and the degradation effect can be maintained until 24 hours after administration.In the subcutaneous transplanted tumor model of OCI-ly10 mice, the tumor growth was completely inhibited by 3mg/kg of HZ-Q1060 administered orally every day for 14 days, which was equivalent to that of ibrutinib 10mg/kg.In the preclinical pharmacokinetic studies, HZ-Q1060 showed excellent pharmacokinetic properties in different species of animals, included mice, rats and beagle dogs, with long T1/2 and high dose-normalized AUC.HZ-Q1060 has no significant CYPs inhibitory effect at 10 μM, so it has a low risk of DDI in the future combination therapy.HZ-Q1060 has no inhibitory effect on hERG channel, indicating the compound has a low potential to induce QT prolongation. HZ-Q1060 also shows good safety and tolerance in the preliminary safety evaluation of animals. Conclusion: In summary, HZ-Q1060 is a potent and selective degrader of BTK with good ADME properties and in vivo efficacy, which makes it suitable for further evaluation in clinical development.

Abstract 5463: BPI-442096: A potent and selective inhibitor of SHP2 for the treatment of multiple cancers

Abstract Src homology region 2 domain-containing phosphatase-2 (SHP-2) is a key node in the RAS signaling pathway. Allosteric inhibition of SHP2 phosphatase is a potential therapeutic strategy for cancers harboring oncogenic mutations in the KRAS pathway. SHP2 also participates in the signal transduction downstream of regulatory immunoreceptors, and it has been shown in preclinical models that SHP2 inhibition drives anti-tumor immunity through modulation of both innate and adaptive mechanism. BPI-442096 is a potent, selective, and orally bioavailable small molecule SHP2 inhibitor. It exhibited significant anti-proliferation activities against multiple KRAS mutant cancer cell lines, including those from NSCLC, PDAC, CRPC, etc. BPI-442096 dose-dependently inhibited SHP2 phosphatase and downstream ERK phosphorylation in cancer cells, as well as NFAT reporter gene expression downstream of PD-1/PD-L1 signaling in immune cells. In vivo, BPI-442096 demonstrated strong tumor growth inhibition in KRASG12C, KRASG12D, and KRASG12V mutant xenograft mouse models. BPI-442096 also exhibited anti-tumor immunity in the MC38 syngeneic model, as a single agent or in combination with anti-PD1/PD-L1 drugs. Moreover, BPI-442096 combining with KRASG12C inhibitor may reverse intrinsic and acquired resistance to KRASG12C inhibition. Adequate oral exposure across multiple pre-clinical species and good ADME properties ensured the druggability of BPI-442096. In conclusion, BPI-442096 exhibits a robust anti-tumor effect in multiple KRAS mutant models and enhanced anti-cancer immunity in syngeneic mouse models, and it shows multiple combination potentials to overcome drug resistance. Phase 1 clinical trial is planned in early 2022. Citation Format: Ling Li, Bang Fu, Han Han, Zhongxin Sun, Xiangdong Zhao, Xuepeng Jv, Jun Tong, Jiayu Zhao, Zhengyao Zou, Haibo Chen, Xiaoyun Liu, Wei Ren, Yinlong Li, Wenmao Wu, Jing Guo, Dan Yan, Xiangyong Liu, Hong Lan, Hao Wu, Lieming Ding, Jiabing Wang. BPI-442096: A potent and selective inhibitor of SHP2 for the treatment of multiple cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5463.

Abstract 6368: Discovery of potent, orally bioavailable, SOS1 inhibitors for KRAS-driven tumors

Abstract KRAS is an oncogene implicated in a wide variety of tumors (~21% of solid tumors harbor KRAS mutations). KRAS interaction with Guanidine Exchange Factors (GEFs) is crucial for its activation, with SOS1 being the predominant GEF. SOS1 inhibition is thus expected to be an effective strategy for targeting the downstream signaling pathway, resulting in anti-proliferative activity in RAS-driven cancers. We have identified multiple potent and selective SOS1 inhibitors, demonstrating significant reduction of GEF activity in a dose-dependent manner. The lead compounds show anti-proliferative activity across a panel of WT and mutant KRAS cell lines, and are synergistic with MAPK pathway inhibitors including KRASG12C inhibitor Sotorasib. Correspondingly, significant reduction in PD biomarkers, pERK and pAKT is demonstrated in KRAS mutant cell lines. PK-PD correlation is also established in a tumor bearing mice model, with dose-dependent reduction of both pERK and pAKT. The lead compound shows good ADME properties, and is orally bioavailable, making it amenable for further in vivo profiling. Citation Format: Sanjita Sasmal, Sukanya Patra, Venkatesham Boorgu, Mahesh Yanamadra, Ashok Ettam, Nagaraju Dunaboyina, Githavani Kummari, Ram Mohan Yengala, Balakrishna Lakhavath, Jayita Das, Satheesh Sunkanapally, Pravalika Reddy, Megha Mariam Mathew. Discovery of potent, orally bioavailable, SOS1 inhibitors for KRAS-driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6368.

Abstract LB117: Identification of novel SOS1-K-Ras disruptors for NSCLC and colon cancers with K-Ras mutation

Abstract KRAS along with other RAS genes represents the most prevalent oncogene in human cancers. Atypical Ras signaling has been identified in more than 30% of all human cancers with the most common being lung, colon, and pancreatic cancers. In particular, K-Ras has been identified as the most important Ras protein in cancer research, implicated in over 21% of human cancers. Current strategies drug only specific K-Ras mutants, leaving open an unmet need for new agents that can address a broader patient population. A new opportunity is emerging for the development of a therapeutic Pan Ras inhibitor by targeting the upstream guanine nucleotide exchange factor (GEF) protein SOS (Son of sevenless). Disruption of SOS1- K-Ras mutant interaction is a good strategy to inhibit activation of mutant K-Ras. SOS1 inhibition through the protein-protein interaction (PPI) disruption assists in keeping K-Ras in the GDP inactive, rather than its active GTP-bound state. Inhibition of SOS1 results in blockade of the RAS-MEK-ERK pathway and lowering proliferation, in both WT and all mutant Ras forms. Here we discuss our approach to target SOS1 to control aberrant Ras signaling in NSCLC and colon cancers. We report the identification of novel potent SOS1-K-Ras disruptors using the SOS1-K-Ras PPI TR-FRET assay. Multiple series have been identified, with a good SAR trend. We have identified low nanomolar potent compounds that translate to modulation of p-ERK in cell based assays in K-Ras mutant cell lines. These compounds exhibited good ADME properties like solubility and metabolic stability. Further profiling of these compounds is ongoing. Citation Format: Sanjita Sasmal, Anuradha Ramanathan, Venkatesham Boorgu. Identification of novel SOS1-K-Ras disruptors for NSCLC and colon cancers with K-Ras mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB117.

Design, synthesis, characterization, crystal structure, Hirshfeld surface analysis, DFT calculations, anticancer, angiogenic properties of new pyrazole carboxamide derivatives

The present study demonstrate the utility of a reverse ligand similarity based approach to identify potential targets for a new series of synthesized pyrazole carboxamides that shows potent anticancer activities against MCF-7 cells compared to other structurally related molecules and controls. Molecular docking studies revealed that the compound 5b interacted very strongly with human estrogen receptor with docking score of -8.82kcal/mol. In case of hERα-LBD, it interacted very well via hydrogen bond with Thr347 with docking score of -8.19 kcal/mol and very good binding with Asp351 via both hydrogen bonding and salt bridge. These results indicate that compound 5b act as better inhibitor for estrogen receptors comparable with the standard inhibitor tamoxifen. Further, ADMET studies reveal that the synthesized compounds have good ADME properties as compared with the data from 95% of drugs readily available in the market. The compound possesses three dimensional supramolecular self-assembly, in which N—H•••O bonds connects the molecules and build up two dimensional arrays, which are extended to 3D network through C—H•••Cg and C—Cl•••Cg interactions. The structure also exhibits π•••π stacking interactions, which contributes to the crystal packing. The Hirshfeld surface analysis was carried out to quantify the intermolecular interactions involved in the crystalline environment. We further optimized the molecular geometry of the compound 5d by DFT method with B3LYP hybrid functional and 6-311+G(d,p) basis set. The optimized structure is in good agreement with the experimental findings. The electrostatic potential map was plotted to understand the energy distribution and chemical reactive regions of the molecule.

Discovery of BIIB068: A Selective, Potent, Reversible Bruton's Tyrosine Kinase Inhibitor as an Orally Efficacious Agent for Autoimmune Diseases.

Autoreactive B cell-derived antibodies form immune complexes that likely play a pathogenic role in autoimmune diseases. In systemic lupus erythematosus (SLE), these antibodies bind Fc receptors on myeloid cells and induce proinflammatory cytokine production by monocytes and NETosis by neutrophils. Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that signals downstream of Fc receptors and plays a transduction role in antibody expression following B cell activation. Given the roles of BTK in both the production and sensing of autoreactive antibodies, inhibitors of BTK kinase activity may provide therapeutic value to patients suffering from autoantibody-driven immune disorders. Starting from an in-house proprietary screening hit followed by structure-based rational design, we have identified a potent, reversible BTK inhibitor, BIIB068 (1), which demonstrated good kinome selectivity with good overall drug-like properties for oral dosing, was well tolerated across preclinical species at pharmacologically relevant doses with good ADME properties, and achieved >90% inhibition of BTK phosphorylation (pBTK) in humans.

Structure-Based and Property-Driven Optimization of N-Aryl Imidazoles toward Potent and Selective Oral RORγt Inhibitors.

Retinoic acid receptor-related orphan receptor gamma-t (RORγt) is considered to be the master transcription factor for the development of Th17 cells that produce proinflammatory cytokines such as IL-17A. Overproportionate Th17 cell abundance is associated with the pathogenesis of many inflammatory conditions including psoriasis. In a high-throughput fluorescence resonance energy transfer (FRET) screen, we identified compound 1 as a hit with promising lipophilic efficiency (LipE). Using structure-based drug design based on a number of X-ray cocrystal structures, we morphed this hit class into potent imidazoles, exemplified by compound 3. To improve the poor absorption, distribution, metabolism, and excretion (ADME) properties of neutral imidazoles, we extended our ligands with carboxylic acid substituents toward a polar, water-rich area of the protein. This highly lipophilicity-efficient modification ultimately led to the discovery of compound 14, a potent and selective inhibitor of RORγt with good ADME properties and excellent in vivo pharmacokinetics. This compound showed good efficacy in an in vivo delayed-type hypersensitivity pharmacology model in rats.

DESIGN, SYNTHESIS, DOCKING, ANTITUMOR SCREENING, AND ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION PREDICTION OF NEW HESPERDIN DERIVATIVE

Objective: Hesperidin (HSP) is a pharmacologically active organic compound found in citrus fruits and peppermint. We synthesized a new HSP derivative by reacting it with 5-Amino-1,3,4-thiadiazole-2-thiol in acetic acid.&#x0D; Methods: This compound was characterized by Fourier-transform infrared, proton nuclear magnetic resonance, and electron impact mass spectra. A molecular docking study explores the predicted binding of the compound and its possible mode of action. Bioavailability, site of absorption, drug mimic, and topological polar surface was predicted using absorption, distribution, metabolism, and excretion (ADME) studies.&#x0D; Results: The docking study predicts that the new compound binds to the active sites of Aurora-B and the MST3 pocket and has good ADME properties. Moreover, the thiazole ring and the presence of the electron releasing groups and hydrogen bond interaction with amino acid residues within the active sites play an important role in enhancing the antioxidant activity.&#x0D; Conclusion: In the present study, a new HSP derivative has been synthesized and characterized successfully and a theoretically promising antioxidant and anticytotoxic active agent introduced. We have shown the detailed binding analysis of 1,3,4-thiadiazol and hydrogen bonds with the inhibitor binding cavity of Aurora B and MST3. This could provide the development of some effective compounds against different diseases.

Rv0807, a putative phospholipase A2 of Mycobacterium tuberculosis; Elucidation through sequence analysis, homology modeling, molecular docking and molecular dynamics studies of potential substrates and inhibitors

Mycobacterium tuberculosis (Mtb) has the ability to scrounge off the host macrophages and create a cordial environment for its survival. Identification of mechanisms favoring this purpose leads to novel treatment strategies for tuberculosis. In this study through in silico approaches, we intend to identify the putative role for Rv0807 from Mtb and its essentiality for mycobacterium survival within the macrophages. Through sequence analysis, we hypothesize that Rv0807 could be a Phospholipase A2 of Mtb. Moreover, through in silico mutation studies we have predicted certain residues to be a part of the catalytic process of the Rv0807 homodimer. Rv0807 could be a potential drug target as it binds phosphatidylinositol-3-phosphate (PI3P) and could be involved in processing the host cell PI3Ps, thereby blocking the phagosomal maturation. A pharmacophore hypothesis was generated for the Rv0807 homodimer based on the ligand binding site and a set of Pretomanid related compounds were screened against the Rv0807 homodimer. The top five compounds which had better docking scores and good ADME properties were selected as best inhibitory compounds and analyzed further. Molecular dynamics (MD) studies of Rv0807 homodimer with PI3P and with the top scored compound in docking studies, demonstrated a lot of conformational changes in the protein structure as it gets occluded through the course of simulation. The movement of a loop atop the ligand binding site, suggests of a lid-like region as seen in many other phospholipases. MD simulation of the mutant structures was also performed and its effect on the protein conformational changes was discussed.Communicated by Ramaswamy H. Sarma

Scaffold Morphing Identifies 3-Pyridyl Azetidine Ureas as Inhibitors of Nicotinamide Phosphoribosyltransferase (NAMPT).

Small molecules that inhibit the metabolic enzyme NAMPT have emerged as potential therapeutics in oncology. As part of our effort in this area, we took a scaffold morphing approach and identified 3-pyridyl azetidine ureas as a potent NAMPT inhibiting motif. We explored the SAR of this series, including 5 and 6 amino pyridines, using a convergent synthetic strategy. This lead optimization campaign yielded multiple compounds with excellent in vitro potency and good ADME properties that culminated in compound 27.

In silico structural anatomization of spleen tyrosine kinase inhibitors: Pharmacophore modeling, 3D QSAR analysis and molecular docking studies

To design a new therapeutic agent for Spleen Tyrosine Kinase (Syk), analysis of ligand-based pharmacophore modeling, 3D QSAR and molecular docking studies were performed. A consortium of 99 molecules with different molecular scaffolds (9.36 > pIC50>5.49) were gathered. Generated models were anatomized and essential properties required for the inhibition of Syk were assimilated. Comparative analyses of highly active, moderately active and inactive molecules helped in explaining the interactions necessary for ligand receptor binding. Further, model validation by collating the crystal structures of Syk also proved its applicability. Based on the analysis, imidazopyrazine based ligands show a strong binding affinity towards Syk active site along with good ADME properties. Going forward this study may pave a new way for designing and synthesising Syk inhibitors with better biological activities.

A Peripherally Selective CB1 Receptor Inverse Agonist Improves Metabolic Syndrome in Mice

The type 1 cannabinoid receptor (CB1) can be targeted to treat major diseases like type 2 diabetes, fibrosis and steatohepatitis. This has led to the development and profiling of several CB1 antagonists; one such drug being rimonabant, a CNS penetrating inverse agonist, for the treatment of obesity. However, rimonabant was discontinued due to CNS‐related adverse psychiatric effects in a subset of patients. Accumulating evidence indicates that peripheral blockade of CB1 with antagonists that have limited brain penetration is an attractive strategy to treat various disorders. Our research has identified RTI‐1092663, a peripherally selective purine‐based inverse agonist with limited brain penetration (~1% of plasma concentration) and good ADME properties, as a therapeutic agent for the treatment of metabolic syndrome. C57/BL6J male mice were fed a standard chow or high fat diet (60% fat calories) from 6 – 24 weeks and were administered vehicle or RTI‐1092663 at doses of 0.1, 0.3 or 1.0mg/kg, PO/day from weeks 20–24. Oral glucose tolerance test was performed 3 days prior to euthanasia. High fat diet (HFD) significantly increased body weight, liver weights and blood glucose levels in both fasted and fed states. HFD also increased hepatic mRNA expression of CXCR1. Treatment with RTI‐1092663 resulted in a significant decline in body weight and liver weight. Further, RTI‐1092663 treatment lowered fasting glucose levels and demonstrated a dose dependent improvement in glucose tolerance. This compound also inhibited increased neutrophil infiltration as demonstrated by a significant decline in CXCR1 mRNA expression. These data suggest that compound RTI‐1092663 could be further developed for the treatment of metabolic syndrome and other diseases.Support or Funding Information1R01AA023256‐011R01DK100414‐01A1This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Synthesis of pyrazole-substituted chromene analogues with selective anti-leukemic activity

We report design and synthesis of a series of flavanone/chromene derivatives containing pyrazoles 6a–6h and 8a–8e with potent anti-leukemic activity. Anti-leukemic activity of novel flavanone derivatives was tested using the K562 cell line. The parental flavanone was selected as the reference compound in identification of analogues with superior anti-leukemic activity. More than two-thirds of the derivatives displayed higher activity than the initial flavanone. Positions of substituents that promoted anti-leukemic activity were identified on both the chromene and pyrazole fragments. Compounds 6b and 6c showed the highest activity against K562 cell line, with IC50 values 3.0 and 0.5 μM respectively. Notably, compounds 6b and 6c displayed very high selectivity in inhibition of leukemic cells (K562) but not of healthy HEK293 cells or solid cancer cell lines HeLa, MCF7 and BT474. Moreover, both the 6b and 6c compounds were predicted to have good ADME properties.