References
- Roskoski R. Properties of FDA-approved small molecule protein kinase inhibitors: a 2021 update. Pharmacol Res. 2021;165:105463.
- Wang PF, Qiu HY, Wang ZF, et al. Identification of novel B-RafV600E inhibitors employing FBDD strategy. Biochem Pharmacol. 2017;132:63–76.
- Patterson H, Nibbs R, McInnes I, et al. Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases. Clin Exp Immunol. 2014;176(1):1–10.
- Perl A. Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases. Nat Rev Rheumatol. 2016;12(3):169–182.
- Al-Ashmawy AA, Elokely KM, Perez-Leal O, et al. Discovery and SAR of novel disubstituted quinazolines as dual PI3Kalpha/mTOR inhibitors targeting breast cancer. ACS Med Chem Lett. 2020;11(11):2156–2164.
- Hua H, Kong Q, Zhang H, et al. Targeting mTOR for cancer therapy. J Hematol Oncol. 2019;12(1):1–19.
- Zaytseva YY, Valentino JD, Gulhati P, et al. mTOR inhibitors in cancer therapy. Cancer Lett. 2012;319(1):1–7.
- Liu J, Wu DC, Qu LH, et al. The role of mTOR in ovarian neoplasms, polycystic ovary syndrome, and ovarian aging. Clin Anat. 2018;31(6):891–898.
- Bathina S, Das UN. Dysregulation of PI3K-Akt-mTOR pathway in brain of streptozotocin-induced type 2 diabetes mellitus in Wistar rats. Lipids Health Dis. 2018;17(1):1–11.
- Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493(7432):338–345.
- Dazert E, Hall MN. mTOR signaling in disease. Curr Opin Cell Biol. 2011;23(6):744–755.
- Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–293.
- Martini M, De Santis MC, Braccini L, et al. PI3K/AKT signaling pathway and cancer: an updated review. Ann Med. 2014;46(6):372–383.
- Teng QX, Ashar YV, Gupta P, et al. Revisiting mTOR inhibitors as anticancer agents. Drug Discov Today. 2019;24(10):2086–2095.
- Zarogoulidis P, Lampaki S, Turner JF, et al. mTOR pathway: a current, up-to-date mini-review. Oncol Lett. 2014;8(6):2367–2370.
- Marquard FE, Jücker M. PI3K/AKT/mTOR signaling as a molecular target in head and neck cancer. Biochem Pharmacol. 2020;172:113729.
- Zask A, Verheijen JC, Richard DJ. Recent advances in the discovery of small-molecule ATP competitive mTOR inhibitors: a patent review. Expert Opin Ther Pat. 2011;21(7):1109–1127.
- Rodon J, Dienstmann R, Serra V, et al. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol. 2013;10(3): 143–153.
- Tian T, Li X, Zhang J. mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy. Int J Mol Sci. 2019;20(3):755.
- Lamming DW, Ye L, Sabatini DM, et al. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest. 2013;123(3):980–989.
- Antonio TM, Jose CJ, Benito I, et al. The Akt-mTOR pathway in Down’s syndrome: the potential use of rapamycin/rapalogs for treating cognitive deficits. CNS & Neurol Disord Drug Targets. 2014;13(1):34–40.
- Waldner M, Fantus D, Solari M, et al. New perspectives on mTOR inhibitors (rapamycin, rapalogs and TORKinibs) in transplantation. Br J Clin Pharmacol. 2016;82(5):1158–1170.
- Fogel AL, Hill S, Teng JM. Advances in the therapeutic use of mammalian target of rapamycin (mTOR) inhibitors in dermatology. J Am Acad Dermatol. 2015;72(5):879–889.
- Roskoski JR. Properties of FDA-approved small molecule protein kinase inhibitors. Pharmacol Res. 2019;144:19–50.
- Meng L, Zheng XS. Toward rapamycin analog (rapalog)-based precision cancer therapy. Acta Pharmacol Sin. 2015;36(10):1163–1169.
- Theilmann W, Gericke B, Schidlitzki A, et al. Novel brain permeant mTORC1/2 inhibitors are as efficacious as rapamycin or everolimus in mouse models of acquired partial epilepsy and tuberous sclerosis complex. Neuropharmacology. 2020;180:108297.
- Liu E, Perl A. Pathogenesis and treatment of autoimmune rheumatic diseases. Curr Opin Rheumatol. 2019;31(3):307.
- Cheng H, Shcherba M, Pendurti G, et al. Targeting the PI3K/AKT/mTOR pathway: potential for lung cancer treatment. Lung cancer management. 2014;3(1):67–75.
- Lisi L, Laudati E, Navarra P, et al. The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype. J Neuroinflammation. 2014;11(1):1–10.
- Zou Z, Tao T, Li H, et al. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. Cell Biosci. 2020;10(1):1–11.
- He Z, Houghton PJ, Williams TM, et al. Regulation of DNA duplication by the mTOR signaling pathway. Cell Cycle. 2021;20:1–10.
- Lee JHS, Vo TT, Fruman DA. Targeting mTOR for the treatment of B cell malignancies. Brit J Clin Pharmaco. 2016;82(5):1213–1228.
- Mendoza MC, Er EE, The Ras-ERK BJ. and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011;36(6):320–328.
- Houghton PJ. Everolimus. Clin Cancer Res. 2010;16(5):1368–1372.
- Rini BI. Temsirolimus, an inhibitor of mammalian target of rapamycin. Clin Cancer Res. 2008;14(5):1286–1290.
- Chang AJ, Sohn R, Lu ZH, et al. Detection of rapalog-mediated therapeutic response in renal cancer xenografts using 64 Cu-bevacizumab immunoPET. PLoS One. 2013;8(3):e58949.
- Steelman LS, Martelli AM, Cocco L, et al. The therapeutic potential of mTOR inhibitors in breast cancer. Br J Clin Pharmacol. 2016;82(5):1189–1212.
- Yu K, Shi C, Toral-Barza L, et al. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res. 2010;70(2):621–631.
- Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/mTOR pathway–beyond rapalogs. Oncotarget. 2010;1(7):530.
- Barda DA, inventor. Imidazo [4, 5 -c] quinolin- 2 -one compound and its use as PI3 kinase/mTOR dual inhibitor. World Patent WO2012097039A1. 2012 Jul 19.
- Kondo S, Tajimi M, Funai T, et al. Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer. Invest New Drugs. 2020;38(6):1836–1845.
- Smith MC, Mader MM, Cook JAI, et al. Characterization of LY3023414, a novel PI3K/mTOR dual inhibitor eliciting transient target modulation to impede tumor growth. Mol Cancer Ther. 2016;15(10):2344–2356.
- Bendell JC, Varghese AM, Hyman DM, et al. A first-in-human phase 1 study of LY3023414, an oral PI3K/mTOR dual inhibitor, in patients with advanced cancer. Clin Cancer Res. 2018;24(14):3253–3262.
- Qing D, inventor. Hexahydrooxazinopterine compounds for use as mTOR inhibitors. World Patent WO2011025889A1. 2011 Mar 3.
- Murphy S, inventor. Substituted oxazinopteridinones as inhibitors of mTOR. World Patent WO2020076728A1. 2020 Apr 16.
- Lynch R, inventor. Morpholino substituted urea derivatives as mTOR inhibitors. World Patent WO2011107585A1. 2011 Sep 9.
- Lynch R, inventor. Morpholino substituted bicyclic pyrimidine urea or carbamate derivatives as mTOR inhibitors. World Patent WO2013050508A1. 2013 Apr 11.
- Cansfield AD, Ladduwahetty T, Sunose M, et al. CZ415, a highly selective mTOR inhibitor showing in vivo efficacy in a collagen induced arthritis model. ACS Med Chem Lett. 2016;7(8):768–773.
- Zhang W, Chen B, Zhang Y, et al. The anti-hepatocellular carcinoma cell activity by a novel mTOR kinase inhibitor CZ415. Biochem Biophys Res Commun. 2017;487(3):494–499.
- Yin G, Fan J, Zhou W, et al. ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activity in vitro and in vivo. Oncotarget. 2017;8(47):82027.
- Kuo MY, inventor. Novel pyrimidine compounds as mTOR and PI3K inhibitors. United States patent US2014178360A1. 2014 Jun 26.
- Guo CX, inventor. Mechanistic target of rapamycin signaling pathway inhibitors and therapeutic applications thereof. World Patent WO2017219800A1. 2017 Dec 28.
- Aranapakam MV, inventor. Triazine compounds as PI3 kinase and mTOR inhibitors. United States patent US2017119778A1. 2017 May 4.
- Braun A, inventor. Pyrimidooxazocine derivatives as m mTOR - inhibitors. World Patent WO2013111106A1. 2013 Aug 1.
- Beaufils F, Cmiljanovic N, Cmiljanovic V, et al. 5-(4, 6-Dimorpholino-1, 3, 5-triazin-2-yl)-4-(trifluoromethyl) pyridin-2-amine (PQR309), a potent, brain-penetrant, orally bioavailable, pan-class I PI3K/mTOR inhibitor as clinical candidate in oncology. J Med Chem. 2017;60(17):7524–7538.
- Wicki A, Brown N, Xyrafas A, et al. First-in human, phase 1, dose-escalation pharmacokinetic and pharmacodynamic study of the oral dual PI3K and mTORC1/2 inhibitor PQR309 in patients with advanced solid tumors (SAKK 67/13). Eur J Cancer. 2018;96:6–16.
- Wicki A, Prêtre V, Ritschard R, et al. Final results of the pharmacodynamic (PD) data of PQR309-001, a first-in-human trial of a combined PI3K/mTOR inhibitor in advanced solid tumors. In: AACR; 2016.
- Cmiljanovic V, inventor. Conformationally restricted PI3K and mTOR inhibitors. World Patent WO2015049369A1. 2015 Apr 9.
- Borsari C, Rageot D, Beaufils F, et al. Preclinical development of PQR514, a highly potent PI3K inhibitor bearing a difluoromethyl–pyrimidine moiety. ACS Med Chem Lett. 2019;10(10):1473–1479.
- Brandt C, Hillmann P, Noack A, et al. The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood-brain barrier and increase seizure threshold in a mouse model of chronic epilepsy. Neuropharmacology 2018;140:107–120.
- Rageot D, Bohnacker T, Keles E, et al. ((S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a potent, orally bioavailable, and brain-penetrable dual inhibitor of class I PI3K and mTOR kinase. J Med Chem. 2019;62(13):6241–6261.
- Singer E, Walter C, Fabbro D, et al. Brain-penetrant PQR620 mTOR and PQR530 PI3K/mTOR inhibitor reduce huntingtin levels in cell models of HD. Neuropharmacology 2020;162:107812.
- Borsari C, Keles E, Rageot D, et al. 4-(Difluoromethyl)-5-(4-((3 R, 5 S)-3, 5-dimethylmorpholino)-6-((R)-3-methylmorpholino)-1, 3, 5-triazin-2-yl) pyridin-2-amine (PQR626), a potent, orally available, and brain-penetrant mTOR inhibitor for the treatment of neurological disorders. J Med Chem. 2020;63(22):13595–13617.
- Cmiljanovic V, inventor. Difluoromethyl-aminopyridines and difluoromethyl-aminopyrimidines. World Patent WO2016075130A1. 2016 May 19.
- Radetich B, inventor. Novel heterocyclic derivatives. World Patent WO2012104776A1. 2012 Aug 9.
- Bravi G, inventor. 6-(morpholin-4-yl)-pyridin-2-yl-1h-pyrrolo[3,2-b]pyridine derivatives as m-TOR inhibitors. World Patent WO2019115640A1. 2019 Jun 20.
- Chresta CM, Davies BR, Hickson I, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 2010;70(1):288–298.
- Shen JK, inventor. Pyridopyrimidine or pyrimidopyrimidine compound, preparation method, pharmaceutical composition and use thereof. World Patent WO2014135028A1. 2014 Sep 12.
- Wagman AS, inventor. Compounds and methods for inhibiting mTOR. World Patent WO2017031427A1. 2017 Feb 23.
- Pike KG, Malagu K, Hummersone MG, et al. Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014. Bioorg Med Chem Lett. 2013;23(5):1212–1216.
- Basu B, Dean E, Puglisi M, et al. First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor AZD2014. Clin Cancer Res. 2015;21(15):3412–3419.
- Powles T, Wheater M, Din O, et al. A randomised phase 2 study of AZD2014 versus everolimus in patients with VEGF-refractory metastatic clear cell renal cancer. Eur Urol. 2016;69(3):450–456.
- Gökmen-Polar Y, Liu Y, Toroni RA, et al. Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral antitumor activity in human breast cancer xenograft models. Breast Cancer Res Treat. 2012;136(3):673–682.
- Laurence C, inventor. mTOR inhibitor compounds. United States patent US2020317683A1. 2020 Oct 8.
- Laurence C, inventor. Novel mTOR inhibitor compounds. United States patent US2020317679A1. 2020 Oct 8.
- Guan HP, inventor. Pyridino[1,2-a]pyrimidone analogue used as mTOR/PI3K inhibitor. World Patent WO2015192761A1. 2015 Dec 23.
- Kenneth DR, inventor. Benzoxazepines as inhibitors of PI3K/mTOR and methods of their use and manufacture. United States patent US2014080810A1. 2014 Mar 20.
- Kenneth DR, inventor. Benzoxazepines as inhibitors of PI3K/mTOR and methods of their use and manufacture. United States patent US2014066431A1. 2014 Mar 6.
- Liu Q, Wang J, Kang SA, et al. Discovery of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl) phenyl) benzo [h][1, 6] naphthyridin-2 (1 H)-one (Torin2) as a Potent, Selective, and Orally Available Mammalian Target of Rapamycin (mTOR) Inhibitor for Treatment of Cancer. J Med Chem. 2011;54(5):1473–1480.
- Wu F, inventor. PI3K and/or mTOR inhibitor. World Patent WO2014040373A1. 2014 Mar 20.
- Wu F, inventor. Pyridonaphthyridine pi3k/mtor dual inhibitors and preparation and use thereof. United States patent US2014093505A1. 2014 Apr 3.
- Meng ZY, inventor. Fused tricyclic inhibitors of mammalian target of rapamycin. World Patent WO2012027234A1. 2012 Mar 1.
- Meng ZY, inventor. Fused tricyclic inhibitors of mammalian target of rapamycin. World Patent WO2012047569A1. 2012 Apr 12.
- Hart S, Novotny-Diermayr V, Goh KC, et al. VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer. Mol Cancer Ther. 2013;12(2):151–161.
- Powles T, Lackner MR, Oudard S, et al. Randomized open-label phase II trial of apitolisib (GDC-0980), a novel inhibitor of the PI3K/mammalian target of rapamycin pathway, versus everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2016;34(14):1660.
- Zhao JZ, inventor. Rafamycin analogs and methods for making same. United States patent US2015051242A1. 2015 Feb 19.
- Semko C, inventor. Rapamycin analogs as mTOR inhibitors. World Patent WO2018204416A1. 2018 Nov 8.
- Rodrik-Outmezguine VS, Okaniwa M, Yao Z, et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016;534(7606):272–276.
- Kuroshima K, Yoshino H, Okamura S, et al. Potential new therapy of Rapalink-1, a new generation mTOR inhibitor, against sunitinib-resistant renal cell carcinoma. Cancer Sci. 2020;111(5):1607.
- La Manna F, De Menna M, Patel N, et al. Dual-mTOR inhibitor Rapalink-1 reduces prostate cancer patient-derived xenograft growth and alters tumor heterogeneity. Front Oncol. 2020;10:1012.
- Pitzen J, inventor. C40-, C28-, and C-32-linked rapamycin analogs as mTOR inhibitors. World Patent WO2019212990A1. 2019 Nov 7.
- Semko C, inventor. C26-linked rapamycin analogs as mTOR inhibitors. World Patent WO2019212991A1. 2019 Nov 7.
- Lawson AP, inventor. mTOR inhibitors and methods of use thereof. World Patent WO2017083823A1. 2017 May 18.
- Gera JF, inventor. Inhibitors of mTOR-ricTOR interactions. World Patent WO2018187414A1. 2018 Oct 11.
- Allen SA, Tomilov A, Cortopassi GA. Small molecules bind human mTOR protein and inhibit mTORC1 specifically. Biochem Pharmacol. 2018;155:298–304.
- Cortopassi G, inventor. mTOR inhibitors and uses thereof. World Patent WO2019178536A1. 2019 Sep 19.
- Ardestani A, Maedler K. mTORC1 and IRS1: another deadly kiss. Trends Endocrinol Metab. 2018;29(11):737–739.
- Formisano L, Napolitano F, Rosa R, et al. Mechanisms of resistance to mTOR inhibitors. Crit Rev Oncol Hematol. 2020;147:102886.
- Zhang X, Wang X, Xu T, et al. Targeting of mTORC2 may have advantages over selective targeting of mTORC1 in the treatment of malignant pheochromocytoma. Tumor Biol. 2015;36(7):5273–5281.