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GSK 2126458, Omipalisib, PI3K/mTOR inhibitor



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GSK 2126458

CAS 1086062-66-9

OMipalisib;GSK2126458;GSK-2126458;GSK2126458 (GSK458);GSK212;




phosphoinositide 3 kinase inhibitor

idiopathic pulmonary fibrosis


MW 505.49598

MF C25H17F2N5O3S


Omipalisib (GSK2126458): Omipalisib, also known as GSK2126458, is a small-molecule pyridylsulfonamide inhibitor of phosphatidylinositol 3-kinase (PI3K) with potential antineoplastic activity. PI3K inhibitor GSK2126458 binds to and inhibits PI3K in the PI3K/mTOR signaling pathway, which may trigger the translocation of cytosolic Bax to the mitochondrial outer membrane, increasing mitochondrial membrane permeability and inducing apoptotic cell death. Bax is a member of the proapoptotic Bcl2 family of proteins. PI3K, often overexpressed in cancer cells, plays a crucial role in tumor cell regulation and survival.

GlaxoSmithKline (GSK) is developing omipalisib (GSK-2126458), a phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor as well as mTOR complex 1 and 2 inhibitor, for the potential oral treatment of cancer and idiopathic pulmonary fibrosis


Certificate of Analysis:

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QC data:

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GSK2126458 is a highly potent PI3K and mTOR inhibitor. In vivo, GSK2126458 showed anti-tumor activity in both pharmacodynamic and tumor growth efficacy models. GSK2126458 reduced the phosphorylated AKT, p70S6K contents in a dose and time dependent way. The IC50 of GSK2126458 is 2 nM for pAKT in the HCC1954 breast carcinoma cell line. In various human tumor cells, GSK2126458 had a width of inhibitory activity for potent cell growth and induced cell death. Notably, GSK2126458 acted mainly by not induction of apoptosis but cell cycle arrest, particularly in G1-phase

GlaxoSmithKline (GSK) is developing omipalisib (GSK-2126458), a phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor as well as mTOR complex 1 and 2 inhibitor, for the potential oral treatment of cancer and idiopathic pulmonary fibrosis

GSK-2126458 is a phosphatidylinositol 3-Kinase (PI3K) inhibitor in early clinical development for the oral treatment of solid tumors and for the oral treatment of lymphoma. Early clinical studies are ongoing for the treatment of idiopathic pulmonary fibrosis. The compound is being developed b GlaxoSmithKline.

In August 2009, a phase I trial began for solid tumors and lymphoma . In April 2012, phase Ib co-clinical trials in advanced prostate cancer (PC) were underway . In March 2013, a phase I trial was initiated in the UK in patients with idiopathic pulmonary fibrosis

In April 2014, a phase I, open-label, multicenter, dose-escalation study (study number P3K113794) and safety data were presented at the 105th AACR meeting in San Diego, CA. Advanced solid tumor patients (n = 69) received oral continuous GSK-2126458 or intermittent GSK-2126458 bid  + trametinib. For GSK-2126458 and trametinib, the MTD in QD cohort was 2 and 1 mg, respectively, and also 1 and 1.5 mg, respectively


Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rampamycin
ACS Med Chem Lett 2010, 1(1): 39


Abstract Image

Phosphoinositide 3-kinase α (PI3Kα) is a critical regulator of cell growth and transformation, and its signaling pathway is the most commonly mutated pathway in human cancers. The mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, is also a central regulator of cell growth, and mTOR inhibitors are believed to augment the antiproliferative efficacy of PI3K/AKT pathway inhibition. 2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide (GSK2126458, 1) has been identified as a highly potent, orally bioavailable inhibitor of PI3Kα and mTOR with in vivo activity in both pharmacodynamic and tumor growth efficacy models. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer.





Figure imgf000151_0002

Figure imgf000145_0002



WO 2008144463

Example 345

2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3- pyridinyl } benzenesulf onamide

a) 6-bromo-4-(4-pyridazinyl)quinoline

Dissolved 6-bromo-4-iodoquinoline (17.43 g, 52.2 mmol), 4- (tributylstannanyl)pyridazine (19.27 g, 52.2 mmol), and PdC12(dppf)-CH2C12 (2.132 g, 2.61 mmol) in 1,4-dioxane (200 mL) and heated to 105 °C. After 3 h, added more palladium catalyst and heated for 6 h. Concentrated and dissolved in methylene chloride/methanol. Purified by column chromatography (combiflash) with 2% MeOH/EtOAc to 5% MeOH/EtOAc to give the crude title compound. Trituration with EtOAc furnished 6-bromo-4-(4-pyridazinyl)quinoline (5.8 g, 20.27 mmol, 38.8 % yield). MS(ES)+ m/e 285.9, 287.9 [M+H]+.

b) 2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3- pyridinyl } benzenesulf onamide A slurry of 6-bromo-4-(4-pyridazinyl)quinoline (4.8 g, 16.78 mmol), bis(pinacolato)diboron (4.69 g, 18.45 mmol) , PdC12(dppf)-CH2C12 (530 mg, 0.649 mmol) and potassium acetate (3.29 g, 33.6 mmol) in anhydrous 1,4-dioxane (120 ml) was heated at 100 °C for 3 h. The complete disappearance of the starting bromide was observed by LCMS. The reaction was then treated with N-[5-bromo-2- (methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (6.68 g, 17.61 mmol) and another portion of PdC12(dppf)-CH2C12 (550 mg, 0.673 mmol), then heated at 110 °C for 16 h. The reaction was allowed to cool to room temperature, filtered, and concentrated. Purification of the residue by chromatography (Analogix; 5% MeOH / 5% CH2C12 / 90% EtOAC) gave 6.5 g (76%) desired product. MS(ES)+ m/e 505.9 [M+H]+.



Intermediate 1  Similar but not same

Scheme A:

Conditions: a) Tributyl(vinyl)tin, Pd(PPh3)4, dioxane, reflux; b) OsO4, NaIO4, 2,6- lutidine, r-BuOH, dioxane, H2O, rt; c) (4-pyridyl)boronic acid, Pd(PPh3)4, 2 M K2CO35 DMF, 100 DC.

4-(4-pyridinyl)-6-quinolinecarbaldehydeSimilar but not same

a) 4-chloro-6-ethenylquinoline

A mixture of 6-bromo-4-chloroquinoline (6.52 g, 26.88 mmol; see J. Med. Chem., H 268 (1978) ), tributyl(vinyl)tin (8.95 g, 28.22 mmol), and tetrakistriphenylphospbine palladium (0) (0.62 g, 0.54 mmol) in 1,4-dioxane (150 mL) was refluxed for 2.0 h, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-4% MeOH:CH2Cl2) to give the title compound (5.1 g) as a pale yellow solid. MS (ES)+ m/e 190 [M+H]+. This material was used directly in the next step.

b) 4-chloro-6-quinolinecarbaldehyde

A mixture of 4-chloro-6-ethenylquinoline (5.1 g, 26.88 mmol), 2,6-lutidine

(5.76 g, 53.75 mmol), sodium (meta) periodate (22.99 g, 107.51 mmol), and osmium tetroxide (5.48 g of a 2.5% solution in tert-butanol, 0.538 mmol) in l,4-dioxane:H2θ (350 mL of 3: 1 mixture) was stirred for 3.5 h at room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (CH2Cb) to give the title compound (4.26 g, 83% for 2 steps) as a pale yellow solid. MS (ES)+ m/e 192 [M+H]+.

c) 4-(4-pyridmyl)-6-qumolinecarbaldehyde

A mixture of 4-chloro-6-quinolinecarbaldehyde (3.24 g, 16.92 mmol), A- pyridylboronic acid (3.12 g, 25.38 mmol), tetrakistriphenylphosphine palladium (0) (0.978 g, 0.846 mmol), and 2M aqueous K2CO3 (7.02 g, 50.76 mmol, 25.4 mis of 2M solution) in DMF (100 mL) was heated at 100 °C for 3.0 h and cooled to room temperature. The mixture was filtered through Celite and the Celite was washed with EtOAc. The filtrate was transferred to a separatory funnel, washed with water and saturated NaCl, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5% MeOH:CH2Cl2) to give the title compound (2.03 g, 51%) as a tan solid. MS (ES)+ m/e 235 [M+H]+.

Intermediate 2

Preparation of 2-amino-5 -bromo-N,N-dimethyl-3 -pyridinesulfonamideSimilar but not same

a) 2-ammo-5-bromo-3-pyridinesulfonyl chloride

To a cooled (0 °C) solution of chlorosulfonic acid (58 mL) under vigorous stirring was added 5-bromo-2-pyridinamine (86.7 mmol) portionwise. The reaction mixture was then heated at reflux for 3 hrs. Upon cooling to room temperature, the reaction mixture was poured over ice (-100 g) with vigorous stirring. The resulting yellow precipitate was collected by suction filtration, washing with cold water and petroleum ether to provide the title compound as an orange-yellow solid (18.1 g, 77% yield). MS(ES)+ m/e 272.8 [M+H]+.

* Other sulfonyl chlorides can be prepared using this procedure by varying the choice of substituted aryl or heteroaryl.

b) 2-amino-5-bromo-N,N-dimethyl-3-pyridinesulfonamide

To a cold (0 DC) suspension of 2-amino-5-bromo-3-pyridinesulfonyl chloride (92.1 mmol) in dry 1,4-dioxane (92 mL) was added pyridine (101.3 mmol) followed by a 2M solution of dimethylamine in THF (101.3 mmol). The reaction was allowed to warm to rt for 2 h, heated to 50 DC for 1 h, then cooled to rt. After standing for 2 h, the precipitate was collected by filtration and rinsed with a minimal amount of cold water. Drying the precipitate to constant weight under high vacuum provided 14.1 g (55%) of the title compound as a white solid. MS(ES)+ m/e 279.8, 282.0 [M+H]+.


Intermediate 3

Preparation of 2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-l,3.2-dioxaborolan-2- yl)-3 -pyridinesulfonamideSimilar but not same

c) To a solution of 2-amino-5-bromo-N,N-dimethyl-3 -pyridinesulfonamide (7.14 mmol) in 1,4-dioxane (35 mL) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-l,3,2- dioxaborolane (7.86 mmol), potassium acetate (28.56 mmol) and [1,1 ‘- bis(diphenylphosphmo)-ferrocene] dichloropalladium(II) dichloromethane complex (1 :1) (0.571 mmol). The reaction mixture was stirred at 100 °C for 18 h. The reaction was concentrated in vacuo, re-dissolved in ethyl acetate (50 mL) and purified on silica using 60% ethyl acetate/hexanes to yield the title compound as a tan solid (86 %). IH ΝMR (400 MHz, DMSOd6) δ ppm 8.41 (d, 1 H, J =1.52), 7.92 (d, 1 H, J = 1.77), 2.68 (s, 6 H), 1.28 (s, 12 H).

* Other boronate or boronic acids can be prepared using this procedure by varying the choice of aryl or heteroaryl bromide. Scheme 17:

Conditions: a) NaO(Rl), (Rl)OH, O 0C to room temperature; b) SnCl2-2H2O, ethyl acetate, reflux; c) (R2)SO2C1, pyridine, O 0C to room temperature.

Intermediate 4

Preparation of N-r5-bromo-2-(methyloxy)-3-pyridinyll-2,4- difluorobenzenesulfonamide

Figure imgf000151_0002N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide

a) 5-bromo-2-(methyloxy)-3-nitropyridine

To a cooled (0 °C) solution of 5-bromo-2-chloro-3-nitropyridine (50 g, 211 mmol) in methanol (200 mL) was added dropwise over 10 minutes 20% sodium methoxide (50 mL, 211 mmol) solution. The reaction, which quickly became heterogeneous, was allowed to warm to ambient temperature and stirred for 16 h. The reaction was filtered and the precipitate diluted with water (200 mL) and stirred for 1 h. The solids were filtered, washed with water (3 x 100 mL) and dried in a vac oven (40 °C) to give 5-bromo-2-(methyloxy)-3-nitropyridine (36 g, 154 mmol, 73.4 % yield) as a pale yellow powder. The original filtrate was concentrated in vacuo and diluted with water (150 mL). Saturated ammonium chloride (25 mL) was added and the mixture stirred for 1 h. The solids were filtered, washed with water, and dried in a vac oven (40 °C) to give a second crop of 5-bromo-2-(methyloxy)-3- nitropyridine (9 g, 38.6 mmol, 18.34 % yield). Total yield = 90%. MS(ES)+ m/e 232.8, 234.7 [M+H]+.

b) 5-bromo-2-(methyloxy)-3-pyridinamine

To a solution of 5-bromo-2-(methyloxy)-3-nitropyridine (45 g, 193 mmol) in ethyl acetate (1 L) was added tin(II) chloride dihydrate (174 g, 772 mmol). The reaction mixture was heated at reflux for 4 h. LC/MS indicated some starting material remained, so added 20 mol% tin (II) chloride dihydrate and continued to heat at reflux. After 2 h, the reaction was allowed to cool to ambient temperature and concentrated in vacuo. The residue was treated with 2 N sodium hydroxide and the mixture stirred for 1 h. The mixture was then with methylene chloride (1 L), filtered through Celite, and washed with methylene chloride (500 mL). The layers were separated and the organics dried over magnesium sulfate and concentrated to give 5-bromo-2-(methyloxy)-3-pyridinamine (23 g, 113 mmol, 58.7 % yield). The product was used crude in subsequent reactions. MS(ES)+ m/e 201.9, 203.9 [M+H]+.

c) N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

Figure imgf000151_0002

To a cooled (0 °C) solution of 5-bromo-2-(methyloxy)-3-pyridinamine (20.3 g, 100 mmol) in pyridine (200 mL) was added slowly 2,4-difluorobenzenesulfonyl chloride (21.3 g, 100 mmol) over 15 min (reaction became heterogeneous). The ice bath was removed and the reaction was stirred at ambient temperature for 16 h, at which time the reaction was diluted with water (500 mL) and the solids filtered off and washed with copious amounts of water. The precipitate was dried in a vacuum oven at 50 °C to give N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide (12 g, 31.6 mmol, 31.7 % yield) MS(ES)+ m/e 379.0, 380.9 [M+H]+.




1. Knight et al., ACS Med. Chem. Lett. 2010, 1, 39-43.
2. Hardwick et al., Mol. Cancer Ther. 2009, 8(12), Supplement I, Abstract C63.
3. Greger et al., Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol. Cancer Ther. 2012, 11(4), 909-920.

1: Zhang Y, Xue D, Wang X, Lu M, Gao B, Qiao X. Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways. Mol Med Rep. 2014 Jan;9(1):83-90. doi: 10.3892/mmr.2013.1781. Epub 2013 Nov 7. PubMed PMID: 24213221.

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3: Kim HG, Tan L, Weisberg EL, Liu F, Canning P, Choi HG, Ezell SA, Wu H, Zhao Z, Wang J, Mandinova A, Griffin JD, Bullock AN, Liu Q, Lee SW, Gray NS. Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor. ACS Chem Biol. 2013 Oct 18;8(10):2145-50. doi: 10.1021/cb400430t. Epub 2013 Aug 13. PubMed PMID: 23899692; PubMed Central PMCID: PMC3800496.

4: Khalili JS, Yu X, Wang J, Hayes BC, Davies MA, Lizee G, Esmaeli B, Woodman SE. Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent manner. Clin Cancer Res. 2012 Aug 15;18(16):4345-55. doi: 10.1158/1078-0432.CCR-11-3227. Epub 2012 Jun 25. PubMed PMID: 22733540; PubMed Central PMCID: PMC3935730.

5: Greger JG, Eastman SD, Zhang V, Bleam MR, Hughes AM, Smitheman KN, Dickerson SH, Laquerre SG, Liu L, Gilmer TM. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther. 2012 Apr;11(4):909-20. doi: 10.1158/1535-7163.MCT-11-0989. Epub 2012 Mar 2. PubMed PMID: 22389471.

6: Wang M, Gao M, Miller KD, Sledge GW, Zheng QH. [11C]GSK2126458 and [18F]GSK2126458, the first radiosynthesis of new potential PET agents for imaging of PI3K and mTOR in cancers. Bioorg Med Chem Lett. 2012 Feb 15;22(4):1569-74. doi: 10.1016/j.bmcl.2011.12.136. Epub 2012 Jan 10. PubMed PMID: 22297110.

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8: Leung E, Kim JE, Rewcastle GW, Finlay GJ, Baguley BC. Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells. Cancer Biol Ther. 2011 Jun 1;11(11):938-46. Epub 2011 Jun 1. PubMed PMID: 21464613; PubMed Central PMCID: PMC3127046.

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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