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Review
. 2021 Jul 22;14(8):710.
doi: 10.3390/ph14080710.

Innovations and Patent Trends in the Development of USFDA Approved Protein Kinase Inhibitors in the Last Two Decades

Mohd Imran  1 , Syed Mohammed Basheeruddin Asdaq  2 , Shah Alam Khan  3 , Dhanalekshmi Unnikrishnan Meenakshi  3 , Abdulhakeem S Alamri  4   5 , Walaa F Alsanie  4   5 , Majid Alhomrani  4   5 , Yahya Mohzari  6 , Ahmed Alrashed  7 , Mohammed AlMotairi  8 , Eman H Alkhaldi  9 , Abeer K Alorabi  10 , Ahmed Subeh Alshrari  11 , Mohammad Tauseef  12 , Abida  1 , Saleh I Alaqel  1 , Ozair Alam  13 , Md Afroz Bakht  14
Affiliations
Review

Innovations and Patent Trends in the Development of USFDA Approved Protein Kinase Inhibitors in the Last Two Decades

Mohd Imran et al. Pharmaceuticals (Basel). .

Abstract

Protein kinase inhibitors (PKIs) are important therapeutic agents. As of 31 May 2021, the United States Food and Drug Administration (USFDA) has approved 70 PKIs. Most of the PKIs are employed to treat cancer and inflammatory diseases. Imatinib was the first PKI approved by USFDA in 2001. This review summarizes the compound patents and the essential polymorph patents of the PKIs approved by the USFDA from 2001 to 31 May 2021. The dates on the generic drug availability of the PKIs in the USA market have also been forecasted. It is expected that 19 and 48 PKIs will be genericized by 2025 and 2030, respectively, due to their compound patent expiry. This may reduce the financial toxicity associated with the existing PKIs. There are nearly 535 reported PKs. However, the USFDA approved PKIs target only about 10-15% of the total said PKs. As a result, there are still a large number of unexplored PKs. As the field advances during the next 20 years, one can anticipate that PKIs with many scaffolds, chemotypes, and pharmacophores will be developed.

Keywords: USFDA; cancer; generic product; inflammation; patent review; protein kinase inhibitors.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Timeline depicting the approval of the PKIs by the USFDA and their primary targets in brackets.
Figure 2
Figure 2
Imatinib mesylate (4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide methanesulfonate).
Figure 3
Figure 3
Gefitinib (N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine).
Figure 4
Figure 4
Erlotinib hydrochloride (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride).
Figure 5
Figure 5
Sorafenib tosylate (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide 4-methylbenzenesulfonate).
Figure 6
Figure 6
Sunitinib malate (N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (2S)-2-hydroxybutanedioic acid).
Figure 7
Figure 7
Dasatinib monohydrate (N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate).
Figure 8
Figure 8
Lapatinib ditosylate monohydrate (N-(3-chloro-4-{[(3-fluorophenyl) methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine bis(4-methylbenzenesulfonate) monohydrate).
Figure 9
Figure 9
Temsirolimus ((3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26- hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone 4′-[2,2-bis(hydroxymethyl)propionate]).
Figure 10
Figure 10
Everolimus ((1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone).
Figure 11
Figure 11
Nilotinib hydrochloride monohydrate (4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide monohydrochloride monohydrate).
Figure 12
Figure 12
Pazopanib hydrochloride (5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride).
Figure 13
Figure 13
Vandetanib (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine).
Figure 14
Figure 14
Vemurafenib (Propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide).
Figure 15
Figure 15
Crizotinib ((R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine).
Figure 16
Figure 16
Ruxolitinib phosphate ((R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate).
Figure 17
Figure 17
Axitinib (N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide).
Figure 18
Figure 18
Bosutinib monohydrate (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile monohydrate).
Figure 19
Figure 19
Regorafenib monohydrate (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate).
Figure 20
Figure 20
Tofacitinib citrate ((3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ß-oxo-1-piperidinepropanenitrile 2-hydroxy-1,2,3-propanetricarboxylate (1:1)).
Figure 21
Figure 21
Cabozantinib (S)-malate (N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamid (2S)-hydroxybutanedioate).
Figure 22
Figure 22
Ponatinib hydrochloride (3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride).
Figure 23
Figure 23
Trametinib dimethyl sulfoxide (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-1H,2H,3H,4H,6H,7H-pyrido[4,3-d]pyrimidin-1-yl}phenyl)acetamide dimethyl sulfoxide).
Figure 24
Figure 24
Dabrafenib mesylate (N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide mesylate).
Figure 25
Figure 25
Afatinib dimaleate (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)but-2-enamide dimaleate).
Figure 26
Figure 26
Ibrutinib (1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one).
Figure 27
Figure 27
Ceritinib (5-Chloro-N4-[2-[(1-methylethyl)sulfonyl]phenyl]-N2-[5-methyl-2-(1-methylethoxy)-4-(4-piperidinyl)phenyl]-2,4-pyrimidinediamine).
Figure 28
Figure 28
Idelalisib (5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one).
Figure 29
Figure 29
Nintedanib esylate (methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate esylate).
Figure 30
Figure 30
Palbociclib (6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one).
Figure 31
Figure 31
Lenvatinib mesylate (4-[3-chloro-4-(N′-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate).
Figure 32
Figure 32
Cobimetinib fumarate ((S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl][3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl]methanone hemifumarate).
Figure 33
Figure 33
Osimertinib mesylate (N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate).
Figure 34
Figure 34
Alectinib hydrochloride (9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride).
Figure 35
Figure 35
Ribociclib succinate (7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide succinate).
Figure 36
Figure 36
Brigatinib (5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine).
Figure 37
Figure 37
Midostaurin (N-[(2S,3R,4R,6R)-3-Methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-N-methylbenzamide).
Figure 38
Figure 38
Neratinib maleate ((E)-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate).
Figure 39
Figure 39
Copanlisib dihydrochloride (2-amino-N-{7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide dihydrochloride).
Figure 40
Figure 40
Abemaciclib (N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]pyrimidin-2-amine).
Figure 41
Figure 41
Acalabrutinib (4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide).
Figure 42
Figure 42
Netarsudil dimesylate ((S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl-2,4-dimethylbenzoate dimesylate).
Figure 43
Figure 43
Baricitinib ({1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile).
Figure 44
Figure 44
Binimetinib (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide).
Figure 45
Figure 45
Dacomitinib monohydrate ((2E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide monohydrate).
Figure 46
Figure 46
Encorafenib (N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl}carbamate).
Figure 47
Figure 47
Fostamatinib disodium hexahydrate (Disodium (6-[[5-fluoro-2-(3,4,5-trimethoxyanilino) pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxo-pyrido[3,2-b][1,4]oxazin-4-yl)methyl phosphate hexahydrate).
Figure 48
Figure 48
Duvelisib hydrate ((S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one hydrate).
Figure 49
Figure 49
Gilteritinib fumarate (2-Pyrazinecarboxamide 6-ethyl-3-[[3-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl] phenyl]amino]-5-[(tetrahydro-2H-pyran-4-yl)amino]-, (2E)-2-butenedioate (2:1)).
Figure 50
Figure 50
Larotrectinib sulfate ((3S)-N-{5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidinecarboxamide sulfate).
Figure 51
Figure 51
Lorlatinib ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-methenopyrazolo[4,3-H][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile).
Figure 52
Figure 52
Entrectinib (N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide).
Figure 53
Figure 53
Upadacitinib hemihydrate ((3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrate (2:1)).
Figure 54
Figure 54
Alpelisib ((2S)-N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidine dicarboxamide).
Figure 55
Figure 55
Erdafitinib (N-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N-{2-[(propan-2-yl)amino]ethyl}quinoxalin-6-amine).
Figure 56
Figure 56
Pexidartinib hydrochloride (5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridin-2-amine monohydrochloride).
Figure 57
Figure 57
Fedratinib dihydrochloride monohydrate (N-tert-butyl-3-{[5-methyl-2-({4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}amino)pyrimidin-4-yl]amino}benzene-1-sulfonamide dihydrochloride monohydrate).
Figure 58
Figure 58
Zanubrutinib ((S)-7-(1-Acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide).
Figure 59
Figure 59
Avapritinib ((S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-yl)pyrimidin-5-yl)ethan-1-amine).
Figure 60
Figure 60
Selumetinib sulfate (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-6-[(2-hydroxyethoxy)carbamoyl]-1-methyl-1H-benzimidazol-3-ium hydrogen sulfate).
Figure 61
Figure 61
Pemigatinib (3-(2,6-difluoro-3,5-dimethoxyphenyl)1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one).
Figure 62
Figure 62
Tucatinib (N6-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-N4-(3-methyl-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}phenyl)quinazoline-4,6-diamine).
Figure 63
Figure 63
Capmatinib dihydrochloride monohydrate (2-fluoro-N-methyl-4-{7-[(quinolin-6-yl)methyl]imidazo[1,2-b][1,2,4]triazin-2-yl}benzamide dihydrochloride monohydrate).
Figure 64
Figure 64
Selpercatinib (6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile).
Figure 65
Figure 65
Ripretinib (1-(4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl)-3-phenylurea).
Figure 66
Figure 66
Pralsetinib ((Cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexane carboxamide).
Figure 67
Figure 67
Trilaciclib dihydrochloride (2′-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one).
Figure 68
Figure 68
Tepotinib hydrochloride monohydrate (3-{1-[(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile hydrochloride monohydrate).
Figure 69
Figure 69
Umbralisib tosylate ((S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one tosylate)).
Figure 70
Figure 70
Tivozanib hydrochloride monohydrate (1-{2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea hydrochloride monohydrate).
Figure 71
Figure 71
Infigratinib phosphate (3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-ethylpiperazin-1-yl)phenylamino]pyrimidin-4-yl}-1-methylurea phosphate).
Figure 72
Figure 72
Summary of the USFDA approved PKIs.
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