An updated patent review of Akt inhibitors (2016-present)

References

• Shariati M, Targeting M-BF. AKT for cancer therapy. Expert Opin Investig Drugs. 2019;28(11):977–988.
   PubMed Web of Science ®Google Scholar
• Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017;169(3):381–405.
   PubMed Web of Science ®Google Scholar
• Bd M, Lc C. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261–1274.
   PubMed Web of Science ®Google Scholar
• Liu P, Cheng H, Roberts TM, et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8(8): 627–644.
   PubMed Web of Science ®Google Scholar
• Xue G, Zippelius A, Wicki A, et al. Integrated Akt/PKB signaling in immunomodulation and its potential role in cancer immunotherapy. J Natl Cancer Inst. 2015;107(7):7.
   Google Scholar
• Lassen A, Atefi M, Robert L, et al. Effects of AKT inhibitor therapy in response and resistance to BRAF inhibition in melanoma. Mol Cancer. 2014;13(1):83.
   PubMedGoogle Scholar
• Testa JR, Bellacosa A. AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A. 2001;98(20):10983–10985.
   PubMed Web of Science ®Google Scholar
• Bellacosa A, Kumar CC, Di Cristofano A, et al. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 2005;94:29–86.
   PubMed Web of Science ®Google Scholar
• Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009;9(1):28–39.
   PubMed Web of Science ®Google Scholar
• Song M, Bode AM, Dong Z, et al. AKT as a Therapeutic Target for Cancer. Cancer Res. 2019;79(6):1019–1031.
   PubMed Web of Science ®Google Scholar
• Li Q. Recent progress in the discovery of Akt inhibitors as anticancer agents. Expert Opin Ther Pat. 2007;17(9):1077–1130.
   Web of Science ®Google Scholar
• Mattmann ME, Stoops SL, Lindsley CW. Inhibition of Akt with small molecules and biologics: historical perspective and current status of the patent landscape. Expert Opin Ther Pat. 2011;21(9):1309–1338.
   PubMed Web of Science ®Google Scholar
• Oliveira M, Saura C, Nuciforo P, et al. FAIRLANE, a double-blind placebo-controlled randomized phase II trial of neoadjuvant ipatasertib plus paclitaxel for early triple-negative breast cancer. Ann Oncol. 2019;30(8):1289–1297.
   PubMed Web of Science ®Google Scholar
• Kim SB, Dent R, Im SA, et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017;18(10):1360–1372.
   PubMed Web of Science ®Google Scholar
• Schmid P, Abraham J, Chan S, et al. AZD5363 plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (PAKT): a randomised, double-blind, placebo-controlled, phase II trial. J Clin Oncol. 2018;36(15_suppl):1007.
   PubMed Web of Science ®Google Scholar
• Vicier C, Isambert N, Dalenc F, et al. TAKTIC: a prospective, multicenter, uncontrolled, phase IB/II study of LY2780301 (LY) in combination with weekly paclitaxel (wP) in HER2-negative locally advanced (LA) or metastatic breast cancer (MBC) patients. J Clin Oncol. 2019;37(15_suppl):1091.
   Web of Science ®Google Scholar
• Aghajanian C, Bell-mcguinn KM, Burris HA, et al. A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors. Invest New Drugs. 2018;36(6):1016–1025.
   PubMed Web of Science ®Google Scholar
• Algazi AP, Esteve-Puig R, Nosrati A, et al. Dual MEK/AKT inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS-mutant and wild-type melanoma. Pigment Cell Melanoma Res. 2018;31(1):110–114.
   PubMed Web of Science ®Google Scholar
• Sangai T, Akcakanat A, Chen H, et al. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clin Cancer Res. 2012;18(20):5816–5828.
   PubMed Web of Science ®Google Scholar
• Xing Y, Lin NU, Maurer MA, et al. Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation. Breast Cancer Res. 2019;21(1):78.
   PubMed Web of Science ®Google Scholar
• Myers AP, Konstantinopoulos PA, Barry WT, et al. Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer. Int J Cancer. 2020;147(2):413–422.
   PubMed Web of Science ®Google Scholar
• Myers AP, Broaddus R, Makker V, et al. Phase II, two-stage, two-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer (EC). J Clin Oncol. 2013;31(15_suppl):5524.
   Web of Science ®Google Scholar
• Gonzalez-Angulo AM, Krop I, Akcakanat A, et al. SU2C phase Ib study of paclitaxel and MK-2206 in advanced solid tumors and metastatic breast cancer. J Natl Cancer Inst. 2015;107(3):dju493.
   PubMedGoogle Scholar
• Chung V, McDonough S, Philip PA, et al. Effect of selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA Oncol. 2017;3(4):516–522.
   PubMed Web of Science ®Google Scholar
• Lu L, Zhang Z, Li G, et al. Dihydropyrazole azepine compound serving as akt inhibitor. WO2017215588A1. 2017.
   Google Scholar
• Lu L, Zhang Z, Li G, et al. Dihydropyrazole azepine compound serving as Akt inhibitor. US10654868. 2020.
   Google Scholar
• Mitchell IS, Blake JF, Xu R, et al. Hydroxylated and methoxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors. US2020345735A1. 2020.
   Google Scholar
• Blake JF, Xu R, Bencsik JR, et al. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. J Med Chem. 2012;55(18): 8110–8127.
   PubMed Web of Science ®Google Scholar
• Lin J, Sampath D, Nannini MA, et al. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res. 2013;19(7):1760–1772.
   PubMed Web of Science ®Google Scholar
• Sugimoto T, Sakamoto T, Yamamoto F, et al. Novel 5h-pyrrolo[2,3-d]pyrimidin-6(7h)-one derivative. WO2017200087A1. 2017.
   Google Scholar
• Iwanowicz EJ Protein kinase regulators. WO2018031987A1. 2018.
   Google Scholar
• Iwanowicz EJ Protein kinase regulators. WO2018031990A1. 2018.
   Google Scholar
• Dong XW, Yang B, Hu Y, et al. Polyfluoro-substituted aromatic heterocyclic derivative, pharmaceutical composition containing same, and applications thereof. WO2018137555A1. 2018.
   Google Scholar
• Liu T, Zhan WH, Wang YM, et al. Structure-based design, synthesis and biological evaluation of diphenylmethylamine derivatives as novel Akt1 inhibitors. Eur J Med Chem. 2014;73:167–176.
   PubMed Web of Science ®Google Scholar
• Zhan WH, Lin SD, Chen J, et al. Design, Synthesis, Biological evaluation, and molecular docking of novel benzopyran and phenylpyrazole derivatives as Akt inhibitors. Chem Biol Drug Des. 2015;85(6):770–779.
   PubMed Web of Science ®Google Scholar
• Zhan WH, Li DQ, Che JX, et al. Integrating docking scores, interaction profiles and molecular descriptors to improve the accuracy of molecular docking: toward the discovery of novel Akt1 inhibitors. Eur J Med Chem. 2014;75:11–20.
   PubMed Web of Science ®Google Scholar
• Dong XW, Zhou XL, Jing H, et al. Pharmacophore identification, virtual screening and biological evaluation of prenylated flavonoids derivatives as PKB/Akt1 inhibitors. Eur J Med Chem. 2011;46(12):5949–5958.
   PubMed Web of Science ®Google Scholar
• Dong XW, Zhan WH, Zhao M, et al. Discovery of 3,4,6-Trisubstituted piperidine derivatives as orally active, Low hERG blocking Akt inhibitors via conformational restriction and Structure-based design. J Med Chem. 2019;62(15): 7264–7288. .
   PubMed Web of Science ®Google Scholar
• Ma CY, Tian H, An J, et al. Akt inhibitor. WO2020156437A1. 2020.
   Google Scholar
• Quambusch L, Landel I, Depta L, et al. Covalent-allosteric inhibitors to achieve Akt Isoform-selectivity. Angew Chem Int Ed Engl. 2019;58(52):18823–18829.
   PubMed Web of Science ®Google Scholar
• Liu X, Long MJC, Hopkins BD, et al. Precision targeting of pten-null Triple-negative breast tumors guided by electrophilic metabolite sensing. ACS Cent Sci. 2020;6(6): 892–902. .
   PubMed Web of Science ®Google Scholar
• Kayser KJ, Glenn MP, Sebti SM, et al. Modifications of the GSK3beta substrate sequence to produce substrate-mimetic inhibitors of Akt as potential anti-cancer therapeutics. Bioorg Med Chem Lett. 2007;17(7):2068–2073.
   PubMed Web of Science ®Google Scholar
• Aye Y, Liu X, Long MJC Akt isozyme-specific covalent inhibitors derived from redox-signaling lipids. WO2018226794A1. 2018.
   Google Scholar
• Sebti SM, Cheng JQ, Hamilton AD, et al. Substrate-mimetic akt inhibitor. US20160369247A1. 2016.
   Google Scholar
• Martin-Acosta P, Xiao X. PROTACs to address the challenges facing small molecule inhibitors. Eur J Med Chem. 2020;210:112993.
   PubMed Web of Science ®Google Scholar
• Pettersson M, Crews CM. PROteolysis TArgeting Chimeras (PROTACs) - Past, present and future. Drug Discov Today Technol. 2019;31:15–27.
   PubMedGoogle Scholar
• Benowitz AB, Jones KL, Harling JD. The therapeutic potential of PROTACs. Expert Opin Ther Pat. 2020;31(1):1-24.• Excellent review of PROTAC disclosed in patents
   Google Scholar
• Jin J, Liu J, Parsons RE, et al. Serine threonine kinase (akt) degradation/disruption compounds and methods of use. WO2019173516A1. 2019.
   Google Scholar
• Gray N, You I, Zhang T, et al. Degradation of akt by conjugation of atp-competitive akt inhibitor gdc-0068 with e3 ligase ligands and methods of use. WO2020210337A1. 2020.
   Google Scholar
• You I, Erickson EC, Donovan KA, et al. Discovery of an AKT degrader with prolonged inhibition of downstream signaling. Cell Chem Biol. 2020;27(1):66–73 e7.
   PubMed Web of Science ®Google Scholar
• Myatt SS, Lam EWF. The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 2007;7(11):847–859.
   PubMed Web of Science ®Google Scholar
• Klempner SJ, Myers AP, Cantley LC. What a tangled web we weave: emerging resistance mechanisms to inhibition of the phosphoinositide 3-Kinase pathway. Cancer Discov. 2013;3(12):1345–1354.
   PubMed Web of Science ®Google Scholar
• Wu D, Yan Y, Wei T, et al. An acetyl-histone vulnerability in PI3K/AKT inhibition-resistant cancers is targetable by both BET and HDAC inhibitors. Cell Rep. 2021;34(7):108744.
   PubMed Web of Science ®Google Scholar
• Lopez JS, Banerji U. Combine and conquer: challenges for targeted therapy combinations in early phase trials. Nat Rev Clin Oncol. 2017;14(1):57–66.
   PubMed Web of Science ®Google Scholar
• Stewart A, Thavasu P, De Bono JS, et al. Titration of signalling output: insights into clinical combinations of MEK and AKT inhibitors. Ann Oncol. 2015;26(7):1504–1510.
   PubMed Web of Science ®Google Scholar
• Revathidevi S, Munirajan AK Akt in cancer: mediator and more. Semin Cancer Biol. 2019;59:80–91.
   PubMed Web of Science ®Google Scholar
• Polivka J, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther. 2014;142(2):164–175.
   PubMed Web of Science ®Google Scholar
• Caponigro G, Horn-spirohn T, Lehar J, et al. Combination therapy. WO2017037578A2. 2017.
   Google Scholar
• Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside. Semin Cancer Biol. 2019;59:125–132.
   PubMed Web of Science ®Google Scholar
• Zhang B, McDonagh C, Huhalov A Combination therapies comprising anti-erbb3 agents. US20180066065A1. 2018.
   Google Scholar
• Dan HC, Jiang K, Coppola D, et al. Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis. Oncogene. 2004;23(3):706–715.
   PubMed Web of Science ®Google Scholar
• Kuchay S, Giorgi C, Simoneschi D, et al. PTEN counteracts FBXL2 to promote IP3R3- and Ca 2+ -mediated apoptosis limiting tumour growth. Nature. 2017;546(7659):554–558.
   PubMed Web of Science ®Google Scholar
• Sebti SM, Pagano M, Kuchay S. Geranylgeranyltransferase I inhibitor for treatment of a pten defective cancer. WO2018226791A1. 2018.
   Google Scholar
• Rothbaum W Methods of treating myeloproliferative neoplasms. WO2019224803A2. 2019.
   Google Scholar
• Kuzu OF, Gowda R, Sharma A, et al. Identification of WEE1 as a target to make AKT inhibition more effective in melanoma. Cancer Biol Ther. 2018;19(1):53–62.
   PubMed Web of Science ®Google Scholar
• Robertson GP, Rgc DORESWAMY, Kuzu OF, et al. Compositions and methods relating to cancer. WO2017078752A1. 2017.
   Google Scholar
• Mj CORNFELD, Kumar R, Sr M. Combination. US20200222431A1. 2020.
   Google Scholar
• Zajac-kaye M, Ra FRANCOIS. Compositions for the treatment of cancer and uses thereof. WO2016209688A1. 2016.
   Google Scholar
• Firestone GL, Kundu A, Aronchik I. Combination therapy for treatment of melanoma. WO2017095826A1. 2017.
   Google Scholar
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674.
   PubMed Web of Science ®Google Scholar
• Fridman WH, Pagès F, Sautès-Fridman C, et al. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306. .
   PubMed Web of Science ®Google Scholar
• Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells. Annu Rev Immunol. 2013;31(1):675–704.
   PubMedGoogle Scholar
• Alissafi T, Banos A, Boon L, et al. Tregs restrain dendritic cell autophagy to ameliorate autoimmunity. J Clin Invest. 2017;127(7):2789–2804.
   PubMed Web of Science ®Google Scholar
• Hu WG, Chen JF Pharmaceutical composition for treating B cell lybphoma. WO2020007087A1. 2020.
   Google Scholar
• Jabbarzadeh Kaboli P, Salimian F, Aghapour S, et al. Akt-targeted therapy as a promising strategy to overcome drug resistance in breast cancer - A comprehensive review from chemotherapy to immunotherapy. Pharmacol Res. 2020;156:104806.
   PubMed Web of Science ®Google Scholar
• Withana NP, Mani A, Sm SINGEL. Treatment of breast cancer using combination therapies comprising an akt inhibitor, a taxane, and a pd-l1 inhibitor. WO2020131765A1. 2020.
   Google Scholar
• Li X, Wenes M, Romero P, et al. Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat Rev Clin Oncol. 2019;16(7):425–441.
   PubMed Web of Science ®Google Scholar
• Jg CROMPTON, Np R. Methods of producing T cell populations using akt inhibitors. WO2017070042A1. 2017.
   Google Scholar
• Chartier-Courtaud C, Fardis M Expansion of tils utilizing akt pathway inhibitors. WO2020096927A1. 2020.
   Google Scholar
• Lewis TS, Law C-L, McEarchern JA Synergistic effects between auristatin-based antibody drug conjugates and inhibitors of the pi3k-akt mtor pathway. US2019184029A1. 2019.
   Google Scholar
• Sasore T, Reynolds AL, Kennedy BN. Targeting the PI3K/Akt/mTOR pathway in ocular neovascularization. In Ash JD, Grimm C, Hollyfield JG, et al. editors. Retinal degenerative diseases. New York, NY:Springer; 2014;805–811.
   Google Scholar
• Zhang ZY, Bao XL, Cong YY, et al. Autophagy in Age-related macular degeneration: a regulatory mechanism of oxidative stress. Oxid Med Cell Longev. 2020;2020:2896036.
   PubMed Web of Science ®Google Scholar
• Jayagopal A, Sinha D Use of akt inhibitors in ophthalmology. WO2020078865A1. 2020.
   Google Scholar
• Sulaiman RS, Basavarajappa HD, Corson TW. Natural product inhibitors of ocular angiogenesis. Exp Eye Res. 2014;129:161–171.
   PubMed Web of Science ®Google Scholar
• Lichtstein D, Buzaglo N Combination of a cardiac steroid and an akt inhibitor for the treatment of cardiovascular diseases and disorders. WO2017109778A1. 2017.
   Google Scholar
• Lichtstein D, Ilani A, Rosen H, et al. Na+, K+-ATPase signaling and bipolar disorder. Int J Mol Sci. 2018;19(8):2314.
   Web of Science ®Google Scholar
• Lu X-H, Dwyer DS. Second-generation antipsychotic drugs, olanzapine, quetiapine, and clozapine enhance neurite outgrowth in PC12 cells via PI3K/AKT, ERK, and pertussis toxin-sensitive pathways. J Mol Neurosci. 2005;27(1):43–64.
   PubMed Web of Science ®Google Scholar
• Shin M, Kim H, Jung J, et al. Pharmaceutical composition for prevention or treatment of neurodegenerative disease. WO2020106048A1. 2020.
   Google Scholar
• Ovadia E, Cohen IR, Herkel J, et al. Use of akt phosphorylation as a biomarker for prognosing neurodegenerative diseases and treating same. US2019204340A1. 2019.
   Google Scholar
• Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168(6):960–976.
   PubMed Web of Science ®Google Scholar
• Cantley LC, Hopkins B, Mukherjee S, et al. Combination therapy for PI3k-associated disease or disorder. WO2019232403A1. 2019.
   Google Scholar
• Lim D, Sh JEONG. Animal model of non-alcoholic liver disease and composition of diagnosis, prevention or treatment for non-alcoholic liver disease. US2020024660A1. 2020.
   Google Scholar
• B-c OH, Jk K, Oh K, et al. Fusion protein of c2 domain and akt kinase domain fragment and use thereof. US2019153051A1. 2019.
   Google Scholar
• Rl NEPPL. Materials and methods for pathologies in muscle following injury, disease or aging. WO2020102802A1. 2020.
   Google Scholar