IntroductionClerodendron infortunatum Linn. (Verbenaceae), commonly known as Bhant in Hindi, is a small shrub occurring throughout the plains of India, which is traditionally used for several medicinal purposes. The aim of the present study was to evaluate the preclinical antihyperglycemic activity of the methanol extract of the leaves of C. infortunatum (MECI) in Wistar rats.MethodsHyperglycemia was induced in rats by a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg body weight). Three days after STZ induction, the hyperglycemic rats were treated with MECI intraperitoneally at the doses of 250 and 500 mg/kg body weight daily for 15 days. Glibenclamide (0.5 mg/kg, orally) was used as a reference drug. The fasting blood glucose levels were measured on every fifth day during the 15 days of treatment. Serum biochemical parameters such as glutamate pyruvate transaminase, glutamate oxaloacetate transaminase, alkaline phosphatase, cholesterol, and total protein were estimated. Antioxidant properties were assessed by estimating hepatic lipid peroxidation, reduced glutathione (GSH), and catalase (CAT).ResultsMECI at the doses of 250 and 500 mg/kg intraperitoneally significantly (P<0.001) and dose-dependently reduced and normalized blood glucose levels as compared to that of the STZ control group. Serum biochemical parameters were significantly (P<0.001) restored towards normal levels in MECI-treated rats as compared to the STZ control. MECI treatment also significantly (P<0.001) decreased lipid peroxidation and recovered GSH levels and CAT activity towards normal values, as compared to the STZ control.ConclusionThe present study demonstrated that the leaves of C. infortunatum had remarkable preclinical antihyperglycemic activity in STZ-induced diabetic rats.

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Streblus asper Lour (Family: Moraceae) is a medicinal plant wildly grows in most part of Asian countries. It has many traditional uses like leprosy, piles, diarrhoea, dysentery, elephantiasis, cancer etc. This present study was relates in terms of behavioural safety and toxicity studies of methanol and petroleum ether extracts of S. asper. Brine Shrimps lethality bioassay method was established for the present study and cytotoxicity was reported in terms of 50% lethality concentration (LC 50 ). Different concentrations of drug solutions were added to the Brine Shrimps, surviving shrimps were counted after 24 h and 50% lethality concentration (LC 50 ) were assessed. Acute toxicity was studied on Swiss albino mice after single dose. Sub-Chronic toxicity was performed for 28 days and assessed with biochemical and histopathological parameters. On cytotoxicity studies of brine shrimps it was found methanol extract of S. asper (MESA) was weakly toxic, may be due to the presence of cardiac glycosides and bioactive compounds, however petroleum ether extract of S. asper (PESA) was non toxic. But, in case of acute and sub-acute toxicity study both extracts were found to be non-toxic.

PRMT5 is a typical type II methyltransferase, transferring two methyl groups to arginine, leading to symmetric dimethylation of the substrate. It can symmetrically methylate histones H2AR3, H3R2, H3R8, and H4R3 and can also methylate many non-histone proteins contributing to tumorigenesis by regulating cell cycle progression, DNA repair, cell growth, apoptosis, and inflammation. Overexpression of PRMT5 is reported in several human malignancies including lymphoma, glioma, melanoma, lung, breast, ovarian, and prostate cancers. Elevated levels correlate with poor prognosis in NSCLC, ovarian cancers, and GBM. Therefore, PRMT5 is considered an attractive target for cancer therapy. We sought to discover and develop PRMT5 inhibitors with the “best-in-class” profile with an emphasis on improved brain permeability for their potential use in solid tumors including glioblastoma. Utilizing structure-guided drug design and SAR-based approaches, we have optimized two chemical series of substrate competitive PRMT5 inhibitors. Determination of co-crystal structures with several de novo designed hits aided in the identification of lead compounds that exhibited potent inhibition of PRMT5. Lead compounds were highly active in inhibiting proliferation of a number of cell lines derived from solid tumors that correlated well with cellular H4R3Me2s inhibition, confirming the mechanism. Lead compounds exhibited desirable drug-like properties including solubility, permeability, lack of CYP inhibition, and pharmacokinetic exposure. A substantial improvement in brain permeability over reported PRMT5 inhibitors was noted in rodent pharmacokinetic studies. In a xenograft model of lung cancer, treatment with lead compounds resulted in significant tumor growth inhibition while correlating with tumor drug levels and modulation of H4R3Me2s as the pharmacodynamic effect. In summary, we have identified PRMT5 inhibitors with “best-in-class" drug-like properties including optimized brain permeability and antitumor efficacy. Evaluation of the efficacy of these lead compounds in additional xenograft models including glioblastoma is currently under way. Citation Format: Dinesh Chikkanna, Sunil Kumar Panigrahi, Sujatha Rajagopalan, Srinivasa Raju Sammeta, Anirudha Lakshminarasimhan, Mohan R, Narasihmarao K, Darshan Chawla, Harsha Bhat, Venkateswarlu Kasturi, Samiulla D.S, Angelene Prasanna, Kiran Aithal, Priyabrata Chand Chand, Naveen Kumar, Sai Sudheer Marri, Srinivasa Rao Ganipisetty, Kasieswara Rao N, Raju Mutyala, Nageswara Rao Neerukattu, Nithesh K, Ramya Amin, Priyanka Machhindra Gorade, Thomas Antony, Girish Daginakatte, Shekar Chelur, Chetan Pandit, Susanta Samajdar, Murali Ramachandra. Novel inhibitors of protein arginine methyltransferase 5 (PRMT5) for the treatment of solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A174.

PRMT5 is a typical type II methyltransferase, transferring two methyl groups to arginine, leading to symmetric dimethylation of the substrate. It can symmetrically methylate histones H2AR3, H3R2, H3R8, and H4R3 and can also methylate many non-histone proteins contributing to tumorigenesis by regulating cell cycle progression, DNA repair, cell growth, apoptosis, and inflammation. Overexpression of PRMT5 is reported in several human malignancies including lymphoma, glioma, melanoma, lung, breast, ovarian, and prostate cancers. Elevated levels correlate with poor prognosis in NSCLC, ovarian cancers, and GBM. Therefore, PRMT5 is considered an attractive target for cancer therapy. We sought to discover and develop PRMT5 inhibitors with the “best-in-class” profile with an emphasis on improved permeability for their potential use in solid tumors. Utilizing structure-guided drug design and SAR-based approaches, we have optimized two chemical series of substrate competitive PRMT5 inhibitors. Determination of co-crystal structures with several de novo designed hits aided in the identification of lead compounds that exhibited potent inhibition of PRMT5. Lead compounds AU-574 and AU-755 were highly active in inhibiting proliferation of a number of cell lines derived from solid tumors that correlated well with cellular H4R3Me2s inhibition, confirming the mechanism. Lead compounds exhibited desirable drug-like properties including solubility, permeability, lack of CYP inhibition, and pharmacokinetic exposure. In xenograft models of Z-138 (lymphoma) and H-358 (lung cancer), treatment with lead compounds resulted in significant tumor growth inhibition while correlating with tumor drug levels and modulation of H4R3Me2s as the pharmacodynamic effect. In summary, we have identified PRMT5 inhibitors with “best-in-class" drug-like properties including optimized permeability and antitumor efficacy. Evaluation of these lead compounds in in vitro selectivity screening and in toxicity studies in higher species is currently under way. Citation Format: Dinesh Chikkanna, Sunil Kumar Panigrahi, Sujatha Rajagopalan, Srinivasa Raju Sammeta, Darshan Chawla, Pavithra S, Samiulla D.S, Angelene Prasanna, Priyabrata Chand, Kiran Aithal, Sai Sudheer Marri, Naveen Kumar, Srinivasa Rao Ganipisetty, Raju Mutyala, Kasieswara Rao, Thomas Antony, Girish Daginakatte, Anirudha Lakshminarasimhan, Mohan R, Narasihmarao K, Shekar Chelur, Chetan Pandit, Susanta Samajdar, Murali Ramachandra. Preclinical In vivo evaluation of efficacy, pharmacokinetics and pharmacodynamics of novel PRMT5 inhibitors in multiple tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1392.