The authors studied the acute effect of caffeine on the levodopa pharmacokinetics and pharmacodynamics in 12 patients with idiopathic Parkinson disease. This double-blind, randomized, crossover study revealed that caffeine shortened the maximal plasma concentration of levodopa, decreased the latency to levodopa walking and tapping motor response, and increased the magnitude of walking response. Caffeine administered before levodopa may improve its pharmacokinetics in some parkinsonian patients.

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.

Introduction: Most of the immunotherapies currently approved in the clinic target immune checkpoint proteins that suppress T-cell responses. There is growing evidence that the innate immune system also plays an important role in the initiation and propagation of enduring antitumor responses. Targeting CD47-SIRPα axis is emerging as one of the promising new immunotherapy approaches that targets innate immune response. A number of clinical trials are in progress to evaluate CD47/SIRPα blocking therapies. Most of these molecules are either anti-CD47 antibodies or SIRPα-Fc recombinant proteins. We are developing a novel small molecule CD47 antagonist, AUR-104, as therapeutic agent for solid and hematalogical cancers. AUR-104 is a CD47 antagonist that disrupts CD47- SIRPα interaction and enhances phagocytosis of tumor cells. AUR-104 exhibits good drug-like properties and demonstrates antitumor activity in several pre-clinical tumor models. Here, we report the anti-tumor efficacy of AUR-104 in combination with tumor specific antibodies in pre-clinical models of cancer and also present the safety profile of AUR-104 in rodents. Materials and Methods: Syngeneic murine tumor models: MC38 colon carcinoma cells were subcutaneously implanted in C57BL/6J mice while A20 B-cell lymphoma cells were implanted in BALB/c mice. Tumor bearing mice were treated with AUR-104 (30 mg/kg, b.i.d, and po) as a single agent or in combination with anti-PD1 antibody (100 µg/animal) or anti-PDL1 antibody (200 µg/animal). Tumor volumes were recorded with calliper's measurement over period of treatment. A single dose maximum tolerated dose (MTD) study in BALB/c mouse followed by a 14-day repeat dose toxicity study in BALB/c mouse: Adult male and female BALB/c, are dosed with AUR-104 at ascending doses up to the limit dose. End points monitored include clinical observations, toxicokinetic parameters, body weights, food consumption, hematology, clinical pathology investigations, organ weights and histopathology of selected tissues. Results: AUR-104 combination treatment with anti-PD1 antibody significantly enhanced anti-tumor efficacy in MC38 colon carcinoma model. Combination study with anti-PDL1 antibody in A20 tumor model is in progress. Preliminary observations from efficacy studies indicate that AUR-104 combination treatments with antibodies are well tolerated without any signs of toxicity. Advance in vitro safety evaluation and in vivo 14 day repeat day toxicity study in mice are being initiated. In summary, AUR-104 plus anti-PD1 antibody was a well-tolerated drug combination that exhibited a much greater in vivo antitumor response as compared to the single agent treatments. These results demonstrate the therapeutic potential of CD47 antagonist AUR-104 in combination with other tumor specific antibodies for the treatment of cancer. Citation Format: Girish Daginakatte, Sasikumar Pottayil, Gundala Chennakrishna, Wesley Roy Balasubramanian, Sudarshan Naremaddepalli, Archana Bhumireddy, Sandeep Patil, Kavitha Nellore, Priyabrata Chand, Kiran Aithal, Amit Dhudashiya, Samiulla DS, Rajesh Eswarappa, Murali Ramachandra. Combination efficacy and safety profile of an orally bioavailable small molecule agent targeting CD47/SIRPα axis [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 3852.