3-ylsulfanyl]-benzothiazol-2-yl}-3-(2-morpholin-4-yl-ethyl)-urea (SAR125844) J. Med Chem
59:7066–7074
51. Romano G, Giordano A (2008) Role of the cyclin-dependent kinase 9-related pathway in
mammalian gene expression and human diseases. Cell Cycle 7(23):3664–3668
52. Dussault I, Bellon SF (2009) From concept to reality: the long road to c-met and RON receptor
tyrosine kinase inhibitors for the treatment of Cancer. Anti Cancer Agents Med Chem
9:221–229
53. Komoto J, Yamada T, Takata Y, Markham GD, Takusagawa F (2004) Crystal structure of the
S-Adenosylmethionine Synthetase ternary complex: a novel catalytic mechanism of
S-Adenosylmethionine synthesis from ATP and met. Biochemistry 43:1821–1831
54. Eathiraj S et al (2011) Discovery of a novel mode of protein kinase inhibition characterized by
the mechanism of inhibition of human Mesenchymal-epithelial transition factor (c-met) protein
autophosphorylation by ARQ 197. J Biol Chem 286(23):20666–20676
55. Coumaran E, Goulaouic H (2015) Selective intravenous inhibitor of the MET tyrosine kinase
SAR125844 inhibits tumor growth in MET-amplified Cancer. Mol Cancer Ther 14(2):384–394
56. Angevin E et al (2017) A first-in-human phase I study of SAR125844, a selective MET tyrosine
kinase inhibitor, in patients with advanced solid tumours with MET amplification. Eur J Cancer
87:131–139
57. Lindmo K, Stenmark H (2006) Regulation of membrane traffic by phosphoinositide 3-kinases. J
Cell Sci 119:605–614
58. Backer JM (2016) The intricate regulation and complex functions of the class III
phosphoinositide 3-kinase Vps34. Biochem J 473(15):2251–2271
59. Stjepanovic G, Baskaran S, Mary G, Lin MG, Hurley JH (2017) Unveiling the role of VPS34
kinase domain dynamics in regulation of the autophagic PI3K complex. Mol Cell Oncol 4(6):
e1367873
60. Bilanges B (2017) Vps34 PI3-kinase inactivation enhances insulin sensitivity through
reprogramming of mitochondrial metabolism. Nat Commun 8(1):1804. https://doi.org/10.
1038/s41467-017-01969-4
61. Honda A et al (2016) Potent, selective, and orally bioavailable inhibitors of VPS34 provide
chemical tools to modulate autophagy in vivo. ACS Med Chem Lett 7:72–76
62. Pasquier B (2016) Autophagy inhibitors. Cell Mol Life Sci 73:985–1001
63. Peppard JV, Ronan B, Pasquier B (2014) Identifying small molecules which inhibit autophagy:
a phenotypic screen using image-based high-content cell analysis. Curr Chem Genom Trans
Med 8(Suppl-1, M2):3–15
64. Pasquier B, El-Ahmad Y, Filoche-Rommé B et al (2015) Discovery of (2S)-8-[(3R)-3Methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2Hpyrimido
[1,2-a]pyrimidin-6-one: a novel potent and selective inhibitor of Vps34 for the treatment of
solid tumors. J Med Chem 58:376–400
65. Pasquier B, Goulaouic H et al (2014) A highly potent and selective Vps34 inhibitor alters
vesicle trafficking and autophagy. Nat Chem Biol 10:1013–1019
66. Pasquier B (2015) SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes
with mTOR inhibition in tumor cells. Autophagy 11(4):725–726
67. Kriplani N, Hermida MA, Brown ER, Leslie NR (2015) Class I PI3-kinases: function and
evolution. Adv Biol Regulation 59:53–64
68. Vadas O, Burke JE, Zhang X, Berndt A, Williams RL (2011) Structural basis for activation and
inhibition of class I Phosphoinositide 3-kinases. Sci Signal 4(195):re2
69. Yu JSL, Cui W (2016) Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR
signaling in pluripotency and cell fate determination. Development 143:3050–3060
70. Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R (2016) Landscape of Phosphatidylinositol3-kinase pathway alterations across 19784 diverse solid tumors. JAMA Oncol 2(12):1565–1573
71. Lengauer C et al (2008) PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci U S A
105(35):13057–13062
122
L. Schio and H. Minoux
59:7066–7074
51. Romano G, Giordano A (2008) Role of the cyclin-dependent kinase 9-related pathway in
mammalian gene expression and human diseases. Cell Cycle 7(23):3664–3668
52. Dussault I, Bellon SF (2009) From concept to reality: the long road to c-met and RON receptor
tyrosine kinase inhibitors for the treatment of Cancer. Anti Cancer Agents Med Chem
9:221–229
53. Komoto J, Yamada T, Takata Y, Markham GD, Takusagawa F (2004) Crystal structure of the
S-Adenosylmethionine Synthetase ternary complex: a novel catalytic mechanism of
S-Adenosylmethionine synthesis from ATP and met. Biochemistry 43:1821–1831
54. Eathiraj S et al (2011) Discovery of a novel mode of protein kinase inhibition characterized by
the mechanism of inhibition of human Mesenchymal-epithelial transition factor (c-met) protein
autophosphorylation by ARQ 197. J Biol Chem 286(23):20666–20676
55. Coumaran E, Goulaouic H (2015) Selective intravenous inhibitor of the MET tyrosine kinase
SAR125844 inhibits tumor growth in MET-amplified Cancer. Mol Cancer Ther 14(2):384–394
56. Angevin E et al (2017) A first-in-human phase I study of SAR125844, a selective MET tyrosine
kinase inhibitor, in patients with advanced solid tumours with MET amplification. Eur J Cancer
87:131–139
57. Lindmo K, Stenmark H (2006) Regulation of membrane traffic by phosphoinositide 3-kinases. J
Cell Sci 119:605–614
58. Backer JM (2016) The intricate regulation and complex functions of the class III
phosphoinositide 3-kinase Vps34. Biochem J 473(15):2251–2271
59. Stjepanovic G, Baskaran S, Mary G, Lin MG, Hurley JH (2017) Unveiling the role of VPS34
kinase domain dynamics in regulation of the autophagic PI3K complex. Mol Cell Oncol 4(6):
e1367873
60. Bilanges B (2017) Vps34 PI3-kinase inactivation enhances insulin sensitivity through
reprogramming of mitochondrial metabolism. Nat Commun 8(1):1804. https://doi.org/10.
1038/s41467-017-01969-4
61. Honda A et al (2016) Potent, selective, and orally bioavailable inhibitors of VPS34 provide
chemical tools to modulate autophagy in vivo. ACS Med Chem Lett 7:72–76
62. Pasquier B (2016) Autophagy inhibitors. Cell Mol Life Sci 73:985–1001
63. Peppard JV, Ronan B, Pasquier B (2014) Identifying small molecules which inhibit autophagy:
a phenotypic screen using image-based high-content cell analysis. Curr Chem Genom Trans
Med 8(Suppl-1, M2):3–15
64. Pasquier B, El-Ahmad Y, Filoche-Rommé B et al (2015) Discovery of (2S)-8-[(3R)-3Methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2Hpyrimido
[1,2-a]pyrimidin-6-one: a novel potent and selective inhibitor of Vps34 for the treatment of
solid tumors. J Med Chem 58:376–400
65. Pasquier B, Goulaouic H et al (2014) A highly potent and selective Vps34 inhibitor alters
vesicle trafficking and autophagy. Nat Chem Biol 10:1013–1019
66. Pasquier B (2015) SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes
with mTOR inhibition in tumor cells. Autophagy 11(4):725–726
67. Kriplani N, Hermida MA, Brown ER, Leslie NR (2015) Class I PI3-kinases: function and
evolution. Adv Biol Regulation 59:53–64
68. Vadas O, Burke JE, Zhang X, Berndt A, Williams RL (2011) Structural basis for activation and
inhibition of class I Phosphoinositide 3-kinases. Sci Signal 4(195):re2
69. Yu JSL, Cui W (2016) Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR
signaling in pluripotency and cell fate determination. Development 143:3050–3060
70. Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R (2016) Landscape of Phosphatidylinositol3-kinase pathway alterations across 19784 diverse solid tumors. JAMA Oncol 2(12):1565–1573
71. Lengauer C et al (2008) PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci U S A
105(35):13057–13062
122
L. Schio and H. Minoux