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Review

PI3Kδ inhibitors for the treatment of cancer: a patent review (2015-present)

, &
Pages 925-941 | Received 20 Sep 2019, Accepted 29 Oct 2019, Published online: 07 Nov 2019

References

  • Norman P. Selective PI3Kd inhibitors, a review of the patent literature. Expert Opin Ther Pat. 2011;21:1773–1790.
  • Garces AE, Stocks MJ. Class 1 PI3K clinical candidates and recent inhibitor design strategies: a medicinal chemistry perspective. J Med Chem. 2019;62:4815–4850.
  • Bui M, Hao X, Shin Y, et al. Synthesis and SAR study of potent and selective PI3Kd inhibitors. Bioorg Med Chem Lett. 2015;25:1104–1109.
  • Vanhaesebroeck B, Waterfield MD. Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res. 1999;253:239–254.
  • Lucas CL, Chandra A, Nejentsev S, et al. PI3Kd and primary immunodeficiencies. Nat Rev Immunol. 2016;16:702–714.
  • Michalovich D, Nejentsev S. Activated PI3 kinase delta syndrome: from genetics to therapy. Front Immunol. 2018;9:369.
  • Jia H, Dai G, Su W, et al. Discovery, optimization, and evaluation of potent and highly selective PI3Kgamma-PI3Kd dual inhibitors. J Med Chem. 2019;62:4936–4948.
  • Vogt PK, Hart JR, Gymnopoulos M. Phosphatidylinositol 3-kinase: the oncoprotein. Curr Top Microbiol Immunol. 2010;347:79–104.
  • Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene. 2008;27:5486–5496.
  • Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497–5510.
  • Wei M, Wang X, Song Z, et al. Targeting PI3Kd: emerging therapy for chronic lymphocytic leukemia and beyond. Med Res Rev. 2015;35:720–752.
  • Katso R, Okkenhaug K, Ahmadi K, et al. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol. 2001;17:615–675.
  • Zirlik K, Veelken H. Idelalisib. Recent Results Cancer Res. 2018;212:243–264.
  • Yang Q, Modi P, Newcomb T, et al. Idelalisib: first-in-class PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and follicular lymphoma. Clin Cancer Res. 2015;21:1537–1542.
  • Shah A, Mangaonkar A. Idelalisib: a novel PI3Kd inhibitor for chronic lymphocytic leukemia. Ann Pharmacother. 2015;49:1162–1170.
  • Vangapandu HV, Jain N, Gandhi V. Duvelisib: a phosphoinositide-3 kinase d/? inhibitor for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017;26:625–632.
  • Flinn IW, O’Brien S, Kahl B, et al. Duvelisib, a novel oral dual inhibitor of PI3K-d?, is clinically active in advanced hematologic malignancies. Blood. 2018;131:877–887.
  • Nastoupil LJ, Lunning MA, Vose JM, et al. Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: a phase 1 dose escalation and expansion trial. Lancet Haematol. 2019;6:e100–9.
  • Burris HA, Flinn IW, Patel MR, et al. Umbralisib, a novel PI3Kd and casein kinase-1e inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018;19:486–496.
  • Cushing TD, Hao X, Shin Y, et al. Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kd inhibitors for inflammation and autoimmune disease. J Med Chem. 2015;58:480–511.
  • Perry MWD, Abdulai R, Mogemark M, et al. Evolution of PI3K? and d inhibitors for inflammatory and autoimmune diseases. J Med Chem. 2019;62:4783–4814.
  • Patel K, Pagel JM. Exploring a future for PI3K inhibitors in chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2019;14:292–301.
  • Moreno O, Butler T, Zann V, et al. Safety, Pharmacokinetics, and pharmacodynamics of ME-401, an oral, potent, and selective inhibitor of phosphatidylinositol 3-kinase P110d, following single ascending dose administration to healthy volunteers. Clin Ther. 2018;40:1855–1867.
  • Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kd inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133:1742–1752.
  • Phillips TJ, Forero-Torres A, Sher T, et al. Phase 1 study of the PI3Kd inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma. Blood. 2018;132:293–306.
  • Shin N, Li YL, Mei S, et al. INCB040093 is a novel PI3Kd inhibitor for the treatment of B cell lymphoid malignancies. J Pharmacol Exp Ther. 2018;364:120–130.
  • Patel L, Chandrasekhar J, Evarts J, et al. Discovery of orally efficacious phosphoinositide 3-kinase d inhibitors with improved metabolic stability. J Med Chem. 2016;59:9228–9242.
  • Shugg RP, Thomson A, Tanabe N, et al. Effects of isoform-selective phosphatidylinositol 3-kinase inhibitors on osteoclasts: actions on cytoskeletal organization, survival, and resorption. J Biol Chem. 2013;288:35346–35357.
  • Ino H, Wilson R, Terao T, et al. Evaluation of the safety, tolerability, and pharmacokinetics of GSK2269557 (Nemiralisib) administered via dry powder inhaler to healthy japanese subjects. Clin Pharmacol Drug Dev. 2019;8:78–86.
  • Down K, Amour A, Baldwin IR, et al. Optimization of novel indazoles as highly potent and selective inhibitors of phosphoinositide 3-kinase d for the treatment of respiratory disease. J Med Chem. 2015;58:7381–7399.
  • Pearson D, Garnier M, Luneau A, et al. 19F-NMR-based determination of the absorption, metabolism and excretion of the oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor leniolisib (CDZ173) in healthy volunteers. Xenobiotica. 2019;49:953–960.
  • Allen RA, Brookings DC, Powell MJ, et al. Seletalisib: characterization of a novel, potent, and selective inhibitor of PI3Kd. J Pharmacol Exp Ther. 2017;361:429–440.
  • Locatelli SL, Careddu G, Serio S, et al. Targeting cancer cells and tumor microenvironment in preclinical and clinical models of hodgkin lymphoma using the dual PI3Kd/? inhibitor RP6530. Clin Cancer Res. 2019;25:1098–1112.
  • Ito Y, Makita S. Tobinai K1. Development of new agents for peripheral T-cell lymphoma. Expert Opin Biol Ther. 2019;19:197–209.
  • Hogg C. Chi-Med initiates first-in-human clinical trial of novel PI3K inhibitor HMPL-689. Hutchicon China Meditech Limited. 2016.
  • Feng YF, Duan WM, Fan S, et al. Synthesis and biological evaluation of 4-(piperid-3-yl)amino substituted 6- pyridylquinazolines as potent PI3Kd inhibitors. Bioorg Med Chem. 2019; 27(19):115035.
  • Erdmann T, Klener P, Lynch JT, et al. Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL. Blood. 2017;130:310–322.
  • Calitor Sciences Llc, Sunshine Lake Rharma Co Ltd. Substituted aminopyrimidine compounds and methods of use. WO2015042078. 2015.
  • Infinity Pharmaceuticals Inc. Heterocyclic compounds and uses thereof. WO2015061204. 2015.
  • Sunshine Lake Pharma Co Ltd, Calitor Sciences Llc. Substituted aminopyrimidine compounds and methods of use. WO2016149160. 2016.
  • Sunshine Lake Pharma Co Ltd, Calitor Sciences Llc. Substituted aminopyrimidine compounds and methods of use. WO2016134668. 2016.
  • Infinity Pharmaceuticals Inc. Heterocyclic compounds and uses thereof. WO2015051241. 2015.
  • Rhizen Pharmaceuticals Sa. Pi3k protein kinase inhibitors, particularly delta and/or gamma inhibitors. WO2015001491. 2015.
  • Gilead Sciences Inc. Phosphatidylinositol 3-kinase inhibitors. WO2015200352. 2015.
  • Neuform Pharmaceuticals Inc. Deuterated compounds for treating hematologic malignant, inflammatory and autoimmune diseases. WO2017087207. 2017.
  • Trustees Of Columbia Univeristy. Compounds, compositionals, and methods for treating T-cell acute lymphoblastic leukemia. WO2019028375. 2019.
  • Fronthera U S Pharmaceuticals Llc. Pi3 kinase inhibitors and uses thereof. WO2019028395. 2019.
  • Korea Res Inst Chemical Tech. Heteroaryl derivative or pharmaceutically acceptable salt thereof, preparation method therefor, and pharmaceutical composition for preventing or treating diseases associated with pi3 kinases, containing same as active ingredient. WO2016204429. 2016.
  • Bioway Inc. Novel quinazolinone derivatives inhibiting pi3k and pharmaceutical composition containing same. WO2018012907. 2018.
  • Yuhan Corp. Quinazoline derivative or its salt and pharmaceutical composition comprising the same. WO2017188720. 2017.
  • Empire Technology Dev Llc. Methods and compositions for treating and preventing dag formation. WO2017087234. 2017.
  • Novartis A. Substituted quinazolin-4-one derivatives. WO2015010641. 2015.
  • Gilead Sciences Inc. Phosphatidylinositol 3-kinase inhibitors. WO2015191752. 2015.
  • Gilead Sciences Inc. Phosphatidylinositol 3-kinase inhibitors. WO2015191745. 2015.
  • Gilead Sciences Inc. Phosphatidylinositol 3-kinase inhibitors. WO2015191726. 2015.
  • Concert Pharmaceuticals Inc. Deuterated phenylquinazolinone and phenylisoquinolinone compounds. WO2015179772. 2015.
  • Suzhou Zelgen Biopharmaceuticals Co Ltd. Deuterated quinazolinone compound and pharmaceutical composition comprising same. WO2015113521. 2015.
  • Neuform Pharmaceuticals Inc. Deuterated compounds for treating blood cancers, and compositions and methods thereof. WO2017079003. 2017.
  • Lupin Ltd. Quinolizinone derivatives as pi3k inhibitors. WO2016001855. 2016.
  • Nanjing Sanhome Pharmaceutical Co Ltd. Substituted pyrimidine compounds as phosphatidylinositol 3-kinase ? inhibitor and use thereof. WO2016141855. 2016.
  • Zhejiang University. Benzothiazine and benzothiadiazine compounds and preparation and use. WO2017133655. 2017.
  • Zhejiang Vimgreen Pharma Ltd. Quinoline analogs as phosphatidylinositol 3-kinase inhibitors. WO2017155741. 2017.
  • Chiesi Farm Spa. Chromene derivatives as phoshoinositide 3-kinases inhibitors. WO2016166239. 2016.
  • Chiesi Farma Spa. Isochromene derivatives as phoshoinositide 3-kinases inhibitors. WO2015091685. 2015.
  • Beigene Ltd. Imidazo [1,5-a] pyrazine derivatives as pi3kdelta inhibitors. WO2018103688. 2018.
  • Beigene Ltd. Imidazo [1,5-a] pyrazine derivatives as pi3kdelta inhibitors. WO2019047915. 2019.
  • Squibb Bristol Myers Co. Heteroaryl substituted pyrrolotriazine amine compounds as pi3k inhibitors. WO2016064958. 2016.
  • Squibb Bristol Myers Co. Bicyclic heteroaryl amine compounds as pi3k inhibitors. WO2016064957. 2016.
  • Chiesi Farm Spa. Pyrazole derivatives as phosphoinositide 3-kinases inhibitors. WO2017134053. 2017.
  • Medivation Technologies Inc. Pyrazolo-, imidazolo- and pyrrolo-pyridine or -pyrimidine derivatives as inhibitors O brutons kinase (btk). WO2015069441. 2015.
  • Outotec Finland Oy. Process for operating a sulfuric acid plant. WO2015058804. 2015.
  • Ye BH. Pyrazolopyrimidine compound as pi3k inhibitor and use thereof. WO2018082444. 2018.
  • Qianwan Pharmaceutical Tech (shenzhen) Co Ltd. Imidazopyridine compound and uses in preparation of pi3k inhibitor. WO2017049498. 2017.
  • Hutchison Medipharma Ltd. Novel heteroaryl and heterocycle compounds, compositions and methods. WO2016119707. 2016.
  • Shanghai Fochon Pharmaceutical Co Ltd. Certain protein kinase inhibitors. WO2016066142. 2016.
  • Hutchison Medipharma Ltd. Novel imidazopyridazine compounds and their use. WO2016045591. 2016.
  • Takeda Pharmaceutical. Azaindole derivatives. WO2015106014. 2015.
  • Takeda Pharmaceutical. Azaindole derivatives. WO2015106012. 2015.
  • Glaxosmithkline Ip Dev Ltd. Chemical compounds. WO2018029126. 2018.
  • Glaxosmithkline Ip Dev Ltd. Oxepinopyrazole derivatives as inhibitors of pi3-kinase activity. WO2018192864. 2018.
  • Daiichi Sankyo Co Ltd. 6-morpholinyl-2-pyrazolyl-9h-purine derivatives and their use as pi3k inhibitors. WO2016157074. 2016.
  • Shanghai Yingli Pharmaceutical Co Ltd. Fused pyrimidine compound, intermediate, preparation method therefor, and composition and application thereof. WO2015043398. 2015.
  • Shanghai Yingli Pharmaceutical Co Ltd. Fused heterocyclic compound, preparation method therefor, pharmaceutical composition, and uses thereof. WO2015055071. 2015.
  • Celon Pharma S A. 7-(morpholin-4-yl)pyrazole[1,5-a]pyrimidine derivatives which are useful for the treatment of immune or inflammatory diseases or cancer. WO2016157091. 2016.
  • Nanjing Gator Meditech Company Ltd, Jilin University. Pyrimidine derivative, cytotoxic agent, pharmaceutical composition and use thereof. WO2016127455. 2016.
  • Merck Sharp & Dohme. Purine inhibitors of human phosphatidylinositol 3-kinase delta. WO2017166104. 2017.
  • Merck Sharp & Dohme. Purine inhibitors of human phosphatidylinositol 3-kinase delta. WO2017000125. 2017.
  • Merck Sharp & Dohme. Purine inhibitors of human phosphatidylinositol 3-kinase delta. WO2016004807. 2016.
  • Merck Sharp & Dohme. Purine inhibitors of human phosphatidylinositol 3-kinase delta. WO2015188369. 2015.
  • Xin M, Zhang SQ, Zhang H, et al. Preparation of 6-arylquinoline compounds as PI3Kd inhibitors for treating inflammation and tumor. CN105237484. 2016.
  • Xin M, Duan W, Feng Y, et al. Introduction of pyrrolidineoxy or piperidineamino group at the 4-position of quinazoline leading to novel quinazoline-based phosphoinositide 3-kinase delta (PI3Kd) inhibitors. J Enzyme Inhib Med Chem. 2018;33:651–656.
  • Xin M, Duan W, Feng Y, et al. Novel 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives as potent phosphoinositide 3-kinase delta (PI3Kd) inhibitors. Bioorg Med Chem. 2018;26:2028–2040.
  • Hei YY, Zhang SQ, Feng Y, et al. Alkylsulfonamide-containing quinazoline derivatives as potent and orally bioavailable PI3Ks inhibitors. Bioorg Med Chem. 2019;27(20):114930.
  • Xin M, Hei YY, Zhang H, et al. Design and synthesis of novel 6-aryl substituted 4-anilinequinazoline derivatives as potential PI3Kd inhibitors. Bioorg Med Chem Lett. 2017;27:1972–1977.
  • Feng Y, Duan W, Fan S, et al. Synthesis and biological evaluation of 4-(piperid-3-yl)amino substituted 6-pyridylquinazolines as potent PI3Kd inhibitors. Bioorg Med Chem. 2019;27:115035.
  • Hefei Inst Physical Sci Cas, Hefei Cosource Pharmaceutical Co Ltd. New pi3k kinase inhibitor. WO2016101553. 2016.
  • Incyte Corp. Heterocyclic compounds as pi3k-gamma inhibitors. WO2017223414. 2017.
  • Dana-farber Cancer Inst Inc. Pyrimido-diazepinone kinase scaffold compounds and methods of treating pi3k-mediated disorders. WO2017177092. 2017.
  • Glaxosmithkline Ip Dev Ltd. Chemical compounds as inhibitors of kinase activity. WO2017137535. 2017.
  • Astrazeneca Ab. 5-[2-(pyridin-2-ylamino)-1,3-thiazol-5-yl]-2,3-dihydro-1H-isoindol-1-one derivatives and their use as dual inhibitors of phosphatidylinositol 3-kinase delta & gamma. WO2018055040. 2018.
  • Merck Sharp & Dohme. Purine inhibitors of human phosphatidylinositol 3-kinase delta. WO2019125839. 2019.
  • Merck Sharp & Dohme. Purine inhibitors of human phosphatidylinositol 3-kinase delta. WO2019119207. 2019.
  • Merck Sharp & Dohme. Purine inhibitors of human phosphatidylinositol 3-kinase delta. WO2019125838. 2019.
  • Merck Sharp & Dohme. Purine inhibitors of human phosphatidylinositol 3-kinase delta. WO2019119206. 2019.
  • Preite S, Gomez-Rodriguez J, Cannons JL, et al. T and B-cell signaling in activated PI3K delta syndrome: from immunodeficiency to autoimmunity. Immunol Rev. 2019;291:154–173.
  • Frustaci AM, Tedeschi A, Deodato M, et al. Duvelisib: a new phosphoinositide-3-kinase inhibitor in chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2019;15:2227–2239.
  • Katsuya H, Cook LBM, Rowan AG, et al. Phosphatidylinositol 3-kinase-d (PI3K-d) is a potential therapeutic target in adult T-cell leukemia-lymphoma. Biomark Res. 2018;6:24.
  • Hoegenauer K, Soldermann N, Hebach C, et al. Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties. Bioorg Med Chem Lett. 2016;26:5657–5662.
  • Dalton SE, Dittus L, Thomas DA, et al. Selectively targeting the kinome-conserved lysine of PI3Kd as a general approach to covalent kinase inhibition. J Am Chem Soc. 2018;140:932–939.
  • Hawkins PT, Stephens LR. PI3K signalling in inflammation. Biochim Biophys Acta. 2015;1851:882–897.

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