41
Views
0
CrossRef citations to date
0
Altmetric
Review

Type II & III inhibitors of tropomyosin receptor kinase (Trk): a 2020–2022 patent update

, , , , , & show all
Pages 231-244 | Received 16 Oct 2023, Accepted 20 May 2024, Published online: 30 May 2024

References

  • Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24(1):677–736. doi: 10.1146/annurev.neuro.24.1.677
  • Kaplan DR, Stephens RM. Neurotrophin signal transduction by the Trk receptor. J Neurobiol. 1994;25(11):1404–1417. doi: 10.1002/neu.480251108
  • Reichardt LF. Neurotrophin-regulated signalling pathways. Philos Trans R Soc B. 2006;361(1473):1545–1564. doi: 10.1098/rstb.2006.1894
  • Valnegri P, Puram SV, Bonni A. Regulation of dendrite morphogenesis by extrinsic cues. Trends Neurosci. 2015;38(7):439–447. doi: 10.1016/j.tins.2015.05.003
  • Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction. Annu Revi Biochem. 2003;72(1):609–642. doi: 10.1146/annurev.biochem.72.121801.161629
  • Ohira K, Hayashi M. A new aspect of the TrkB signaling pathway in neural plasticity. Curr Neuropharmacol. 2009;7(4):276–285. doi: 10.2174/157015909790031210
  • Thoenen H. Neurotrophins and neuronal plasticity. Science. 1995;270(5236):593–598. doi: 10.1126/science.270.5236.593
  • Castrén E, Antila H. Neuronal plasticity and neurotrophic factors in drug responses. Mol Psychiatry. 2017;22(8):1085–1095. doi: 10.1038/mp.2017.61
  • Smeyne RJ, Klein R, Schnapp A, et al. Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature. 1994;368(6468):246–249. doi: 10.1038/368246a0
  • Barbacid M. The Trk family of neurotrophin receptors. J Neurobiol. 1994;25(11):1386–1403. doi: 10.1002/neu.480251107
  • Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25–34. doi: 10.1158/2159-8290.CD-14-0765
  • Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731–747. doi: 10.1038/s41571-018-0113-0
  • Amatu A, Sartore-Bianchi A, Bencardino K, et al. Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer. Ann Oncol. 2019;30(Suppl_8):viii5–viii15. doi: 10.1093/annonc/mdz383
  • Hsiao SJ, Zehir A, Sireci AN, et al. Detection of tumor NTRK gene fusions to identify patients who may benefit from tyrosine kinase (TRK) inhibitor therapy. J Mol Diagn. 2019;21(4):553–571. doi: 10.1016/j.jmoldx.2019.03.008
  • Gatalica Z, Xiu J, Swensen J, et al. Molecular characterization of cancers with NTRK gene fusions. Mod Pathol. 2019;32(1):147–153. doi: 10.1038/s41379-018-0118-3
  • Marchiò C, Scaltriti M, Ladanyi M, et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol. 2019;30(9):1417–1427. doi: 10.1093/annonc/mdz204
  • Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023. doi: 10.1136/esmoopen-2015-000023
  • Tognon C, Knezevich SR, Huntsman D, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2(5):367–376. doi: 10.1016/S1535-6108(02)00180-0
  • Westphalen CB, Krebs MG, Le Tourneau C, et al. Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population. NPJ Precis Oncol. 2021;5(1):69. doi: 10.1038/s41698-021-00206-y
  • Lagadec C, Meignan S, Adriaenssens E, et al. TrkA overexpression enhances growth and metastasis of breast cancer cells. Oncogene. 2009;28(18):1960–1970. doi: 10.1038/onc.2009.61
  • Brodeur GM, Minturn JE, Ho R, et al. Trk receptor expression and inhibition in neuroblastomas. Clin Cancer Res. 2009;15(10):3244–3250. doi: 10.1158/1078-0432.CCR-08-1815
  • Kyker-Snowman K, Hughes RM, Yankaskas CL, et al. TrkA overexpression in non-tumorigenic human breast cell lines confers oncogenic and metastatic properties. Breast Cancer Res Treat. 2020;179(3):631–642. doi: 10.1007/s10549-019-05506-3
  • Griffin N, Marsland M, Roselli S, et al. The receptor tyrosine kinase TrkA is increased and targetable in HER2-positive breast cancer. Biomolecules. 2020;10(9):1329. doi: 10.3390/biom10091329
  • Regua AT, Doheny D, Arrigo A, et al. Trk receptor tyrosine kinases in metastasis and cancer therapy. Discov Med. 2019;28(154):195–203.
  • Descamps S, Pawlowski V, Révillion F, et al. Expression of nerve growth factor receptors and their prognostic value in human breast cancer. Cancer Res. 2001;61(11):4337–4340.
  • Ginsberg SD, Che S, Wuu J, et al. Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer’s disease. J Neurochem. 2006;97(2):475–487. doi: 10.1111/j.1471-4159.2006.03764.x
  • Baydyuk M, Nguyen MT, Xu B. Chronic deprivation of TrkB signaling leads to selective late-onset nigrostriatal dopaminergic degeneration. Exp Neurol. 2011;228(1):118–125. doi: 10.1016/j.expneurol.2010.12.018
  • Gupta VK, You Y, Gupta VB, et al. TrkB receptor signalling: implications in neurodegenerative, psychiatric and proliferative disorders. Int J Mol Sci. 2013;14(5):10122–10142. doi: 10.3390/ijms140510122
  • Tejeda GS, Díaz-Guerra M. Integral characterization of defective BDNF/TrkB signalling in neurological and psychiatric disorders leads the way to new therapies. Int J Mol Sci. 2017;18(2):268. doi: 10.3390/ijms18020268
  • Espinera AR, Ogle ME, Gu X, et al. Citalopram enhances neurovascular regeneration and sensorimotor functional recovery after ischemic stroke in mice. Neuroscience. 2013;247:1–11. doi: 10.1016/j.neuroscience.2013.04.011
  • Middlemas DS, Lindberg RA, Hunter T. trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol Cell Biol. 1991;11(1):143–153. doi: 10.1128/mcb.11.1.143-153.1991
  • Fenner ME, Achim CL, Fenner BM. Expression of full-length and truncated trkB in human striatum and substantia nigra neurons: implications for Parkinson’s disease. J Mol Histol. 2014;45(3):349–361. doi: 10.1007/s10735-013-9562-z
  • Wong J, Higgins M, Halliday G, et al. Amyloid beta selectively modulates neuronal TrkB alternative transcript expression with implications for Alzheimer’s disease. Neuroscience. 2012;210:363–374. doi: 10.1016/j.neuroscience.2012.02.037
  • Eide FF, Vining ER, Eide BL, et al. Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci. 1996;16(10):3123–3129. doi: 10.1523/JNEUROSCI.16-10-03123.1996
  • Haapasalo A, Koponen E, Hoppe E, et al. Truncated trkB.T1 is dominant negative inhibitor of trkB.TK±mediated cell survival. Biochem Biophys Res Commun. 2001;280(5):1352–1358. doi: 10.1006/bbrc.2001.4296
  • Wu J, Renn CL, Faden AI, et al. TrkB.T1 contributes to neuropathic pain after spinal cord injury through regulation of cell cycle pathways. J Neurosci. 2013;33(30):12447–12463. doi: 10.1523/JNEUROSCI.0846-13.2013
  • Di Giovanni S, Movsesyan V, Ahmed F, et al. Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury. Proc Natl Acad Sci USA. 2005;102(23):8333–8338. doi: 10.1073/pnas.0500989102
  • Wei X, Wang L, Hua J, et al. Inhibiting BDNF/TrkB.T1 receptor improves resiniferatoxin-induced postherpetic neuralgia through decreasing ASIC3 signaling in dorsal root ganglia. J Neuroinflammation. 2021;18(1):96. doi: 10.1186/s12974-021-02148-5
  • Cao T, Matyas JJ, Renn CL, et al. Function and mechanisms of truncated BDNF receptor TrkB.T1 in neuropathic pain. Cells. 2020;9(5):1194. doi: 10.3390/cells9051194
  • Hefti FF, Rosenthal A, Walicke PA, et al. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol Sci. 2006;27(2):85–91. doi: 10.1016/j.tips.2005.12.001
  • Indo Y, Tsuruta M, Hayashida Y, et al. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nature Genet. 1996;13(4):485–488. doi: 10.1038/ng0896-485
  • Miranda C, Di Virgilio M, Selleri S, et al. Novel pathogenic mechanisms of congenital insensitivity to pain with anhidrosis genetic disorder unveiled by functional analysis of neurotrophic tyrosine receptor kinase type 1/nerve growth factor receptor mutations. J Biol Chem. 2002;277(8):6455–6462. doi: 10.1074/jbc.M110016200
  • Slater D, Kunnathil S, McBride J, et al. Pharmacology of nonsteroidal antiinflammatory drugs and opioids. Semin Intervent Radiol. 2010;27(4):400–411. doi: 10.1055/s-0030-1267855
  • Patel MK, Kaye AD, Urman RD. Tanezumab: Therapy targeting nerve growth factor in pain pathogenesis. J Anaesthesiol Clin Pharmacol. 2018;34(1):111–116. doi: 10.4103/joacp.JOACP_389_15
  • Zhao D, Luo MH, Pan JK, et al. Based on minimal clinically important difference values, a moderate dose of tanezumab may be a better option for treating hip or knee osteoarthritis: a meta-analysis of randomized controlled trials. Ther Adv Musculoskelet Dis. 2022;14:1759720x211067639. doi: 10.1177/1759720X211067639
  • Miller RE, Malfait AM, Block JA. Current status of nerve growth factor antibodies for the treatment of osteoarthritis pain. Clin Exp Rheumatol. 2017;35 Suppl 107(5):85–87.
  • Paula D, Alan JK, Joseph SG, et al. Efficacy and safety of fasinumab in patients with chronic low back pain: a phase II/III randomised clinical trial. Ann Rheumatic Dis. 2021;80(4):509. doi: 10.1136/annrheumdis-2020-217259
  • Norman BH, McDermott JS. Targeting the nerve growth factor (NGF) pathway in drug discovery. Potential applications to new therapies for chronic pain. J Med Chem. 2017;60(1):66–88. doi: 10.1021/acs.jmedchem.6b00964
  • Bagal SK, Andrews M, Bechle BM, et al. Discovery of potent, selective, and peripherally restricted pan-trk kinase inhibitors for the treatment of pain. J Med Chem. 2018;61(15):6779–6800. doi: 10.1021/acs.jmedchem.8b00633
  • Bertrand T, Kothe M, Liu J, et al. The crystal structures of TrkA and TrkB suggest key regions for achieving selective inhibition. J Mol Biol. 2012;423(3):439–453. doi: 10.1016/j.jmb.2012.08.002
  • Treiber Daniel K, Shah Neil P. Ins and outs of kinase DFG motifs. Chem Biol. 2013;20(6):745–746. doi: 10.1016/j.chembiol.2013.06.001
  • Wu T, Zhang C, Lv R, et al. Design, synthesis, biological evaluation and pharmacophore model analysis of novel tetrahydropyrrolo[3,4-c]pyrazol derivatives as potential TRKs inhibitors. Eur J Med Chem. 2021;223:113627. doi: 10.1016/j.ejmech.2021.113627
  • Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lan Oncol. 2020;21(4):531–540. doi: 10.1016/S1470-2045(19)30856-3
  • Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion–positive cancers in adults and children. N Engl J Med. 2018;378(8):731–739. doi: 10.1056/NEJMoa1714448
  • Cocco E, Lee JE, Kannan S, et al. TRK xDFG mutations trigger a sensitivity switch from type I to II kinase inhibitors. Cancer Discov. 2021;11(1):126–141. doi: 10.1158/2159-8290.CD-20-0571
  • Xiang S, Wang J, Huang H, et al. Switch type I to type II TRK inhibitors for combating clinical resistance induced by xDFG mutation for cancer therapy. Eur J Med Chem. 2023;245:114899. doi: 10.1016/j.ejmech.2022.114899
  • Zhao Z, Wu H, Wang L, et al. Exploration of type II binding mode: a privileged approach for kinase inhibitor focused drug discovery? ACS Chem Biol. 2014;9(6):1230–1241. doi: 10.1021/cb500129t
  • Wang J, Zhou Y, Tang X, et al. JND4135, a new type II TRK inhibitor, overcomes TRK xDFG and other mutation resistance in vitro and in vivo. Molecules (Basel, Switzerland). 2022;27(19). doi: 10.3390/molecules27196500
  • Albaugh P, Fan Y, Mi Y, et al. Discovery of GNF-5837, a selective TRK inhibitor with efficacy in rodent cancer tumor models. ACS Med Chem Lett. 2012;3(2):140–145. doi: 10.1021/ml200261d
  • Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–2308. doi: 10.1158/1535-7163.MCT-11-0264
  • Patwardhan PP, Ivy KS, Musi E, et al. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget. 2016;7(4):4093–4109. doi: 10.18632/oncotarget.6547
  • Yan W, Lakkaniga NR, Carlomagno F, et al. Insights into current tropomyosin receptor kinase (TRK) inhibitors: development and clinical application. J Med Chem. 2019;62(4):1731–1760. doi: 10.1021/acs.jmedchem.8b01092
  • Su H-P, Rickert K, Burlein C, et al. Structural characterization of nonactive site, TrkA-selective kinase inhibitors. Proc Nat Acad Sci. 2017;114(3):E297–E306. doi: 10.1073/pnas.1611577114
  • Allen S, Andrews SW, Blake JF, et al. Pyrrolidinyl urea and pyrrolidinyl thiourea compounds as TrkA kinase inhibitors. WO2012158413. 2012.
  • Martinez R, Defnet A, Shapiro P. Avoiding or co-opting ATP inhibition: overview of type III, IV, V, and VI kinase inhibitors. In: Shapiro P, editor. Next generation kinase inhibitors: moving beyond the ATP binding/catalytic sites. Cham: Springer International Publishing; 2020. p. 29–59.
  • McCarthy C, Walker E. Tropomyosin receptor kinase inhibitors: a patent update 2009 – 2013. Expert Opin Ther Patents. 2014;24(7):731–744. doi: 10.1517/13543776.2014.910195
  • Bailey JJ, Schirrmacher R, Farrell K, et al. Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 – part I. Expert Opin Ther Patents. 2017;27(6):733–751. doi: 10.1080/13543776.2017.1297796
  • Bailey JJ, Schirrmacher R, Farrell K, et al. Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 – part II. Expert Opin Ther Patents. 2017;27(7):831–849. doi: 10.1080/13543776.2017.1297797
  • Bailey JJ, Jaworski C, Tung D, et al. Tropomyosin receptor kinase inhibitors: an updated patent review for 2016–2019. Expert Opin Ther Patents. 2020;30(5):325–339. doi: 10.1080/13543776.2020.1737011
  • Jaworski C, Petar I, Wängler C, et al. Type I inhibitors of tropomyosin receptor kinase (Trk): a 2020-2022 patent update. Expert Opin Ther Pat. 2023 Jul;33(7–8):503–521. doi: 10.1080/13543776.2023.2262136
  • Xiaoyun L, Xun H, Shuang X, et al. Imidazopyridazine derivative and application thereof. CN114989176. 2022.
  • Choi HS, Rucker PV, Wang Z, et al. (R)-2-phenylpyrrolidine substituted imidazopyridazines: a new class of potent and selective pan-TRK inhibitors. ACS Med Chem Lett. 2015;6(5):562–567. doi: 10.1021/acsmedchemlett.5b00050
  • O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16(5):401–412. doi: 10.1016/j.ccr.2009.09.028
  • Lu X, Zhang Z, Ding K, et al. Alkynylphenylbenzamide compound and use thereof. WO2022217821. 2022.
  • Sintim HO, Larocque EA, Hernandez DE, et al. 2,3-Disubstituted pyrido[3,4-b]pyrazine-containing compounds as kinase inhibitors. WO2021262915. 2021.
  • Wang M, Naganna N, Sintim HO. Identification of nicotinamide aminonaphthyridine compounds as potent RET kinase inhibitors and antitumor activities against RET rearranged lung adenocarcinoma. Bioorg Chem. 2019;90:103052. doi: 10.1016/j.bioorg.2019.103052
  • Larocque E, Chu EFY, Naganna N, et al. Nicotinamide–ponatinib analogues as potent anti-CML and anti-AML compounds. ACS Omega. 2020;5(6):2690–2698. doi: 10.1021/acsomega.9b03223
  • Ardini E, Bosotti R, Borgia AL, et al. The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition. Mol Oncol. 2014;8(8):1495–1507. doi: 10.1016/j.molonc.2014.06.001
  • Cheng H, Wen X, Liu Z, et al. Pyridone compound, preparation method therefor, and application thereof. WO2022017524. 2022.
  • Esteban I, Levanti B, Garcia-Suarez O, et al. A neuronal subpopulation in the mammalian enteric nervous system expresses TrkA and TrkC neurotrophin receptor-like proteins. Anat Rec. 1998;251(3):360–370. doi: 10.1002/(SICI)1097-0185(199807)251:3<360:AID-AR12>3.0.CO;2-M
  • Eidam HS, Demartino MP, Gong Z, et al. Pyridine derivatives as rearranged during transfection (RET) kinase inhibitors. WO2014141187. 2014.
  • Liu Q, Liu J, Wang B, et al. New use of indazole compound. WO2021174581. 2021.
  • Liu X, Wang B, Chen C, et al. Discovery of (E)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide (CHMFL-ABL-121) as a highly potent ABL kinase inhibitor capable of overcoming a variety of ABL mutants including T315I for chronic myeloid leukemia. Eur J Med Chem. 2018;160:61–81. doi: 10.1016/j.ejmech.2018.10.007
  • Wang B, Zhang W, Liu X, et al. Discovery of (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (IHMT-TRK-284) as a novel orally available type II TRK kinase inhibitor capable of overcoming multiple resistant mutants. Eur J Med Chem. 2020;207:112744. doi: 10.1016/j.ejmech.2020.112744
  • Zhong B, Zhang TT, Cao Y, et al. Trk inhibitor as anti-cancer drug. WO2020048455. 2020.
  • Konicek BW, Capen AR, Credille KM, et al. Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors. Oncotarget. 2018;9(17):13796–13806. doi: 10.18632/oncotarget.24488
  • Zhong B, Zhang T, Dong C, et al. Abstract 4027: TSN084, a multi-kinase inhibitor, overcomes acquired drug-resistant mutations of cMet, Trks, and Flt3, and displays broad activities against kinase oncotargets Axl, DDRs, and CDK8/19. Cancer Res. 2023;83(7_Supplement):4027–27. doi: 10.1158/1538-7445.AM2023-4027
  • Furuya N, Momose T, Katsuno K, et al. The juxtamembrane region of TrkA kinase is critical for inhibitor selectivity. Bioorganic Med Chem Lett. 2017;27(5):1233–1236. doi: 10.1016/j.bmcl.2017.01.056
  • Zhang Y, Wu W, Li Z, et al. Pyrrolidinyl urea derivatives and application thereof in TrkA-related diseases. WO2020011227. 2020.
  • Hong F, Chen Z, Wang L, et al. Crystal form of pyrrolidinyl urea derivative and application thereof. WO2021139794. 2021.
  • Zhang Y, Wu W, Teng M, et al. Pyrrolidinyl urea derivatives and application thereof. WO2020083377. 2020.
  • Liu J, Wang J, Han X, et al. Tropomyosin receptor kinase (Trk) degradation compounds and methods of use. WO2022218289. 2022.
  • Liu D, Flory J, Lin A, et al. Characterization of on-target adverse events caused by TRK inhibitor therapy. Ann Oncol. 2020;31(9):1207–1215. doi: 10.1016/j.annonc.2020.05.006
  • Wang G, Wu Y, Wu C, et al. Rational design and crystallographic analysis of novel isoform-selective TRKA inhibitors for cancer therapy. Acta Pharm Sin B. 2023;13(1):440–443. doi: 10.1016/j.apsb.2022.10.012
  • Wang Z, Ren J, Jia K, et al. Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor. Eur J Med Chem. 2022;241:114601. doi: 10.1016/j.ejmech.2022.114601
  • Guo J, Xiang S, Wang J, et al. Discovery of novel TrkA allosteric inhibitors: Structure-based virtual screening, biological evaluation and preliminary SAR studies. Eur J Med Chem. 2022;228:114022. doi: 10.1016/j.ejmech.2021.114022
  • Subramanian G, Duclos B, Johnson PD, et al. In pursuit of an allosteric human tropomyosin kinase a (hTrkA) inhibitor for chronic pain. ACS Med Chem Lett. 2021;12(11):1847–1852. doi: 10.1021/acsmedchemlett.1c00483
  • Bagal SK, Omoto K, Blakemore DC, et al. Discovery of allosteric, potent, subtype selective, and peripherally restricted TrkA kinase inhibitors. J Med Chem. 2019;62(1):247–265. doi: 10.1021/acs.jmedchem.8b00280
  • Tang S, Xue Y, Dengqi X, et al. Design, development and evaluation of a prodrug-type TrkA-selective inhibitor with antinociceptive effects in vivo. Eur J Med Chem. 2023;245:114901. doi: 10.1016/j.ejmech.2022.114901
  • Nordvall G, Dahlström M, Parrado-Fernandez C, et al. Negative allosteric modulators of TrkA for the treatment of pain. In: International Association for the Study of Pain (IASP), 2021 Jun 27 - Jul 02; Amsterdam; 2021.
  • Cui J, Xiao Z, Zhang LL. Clinical efficacy and safety of nazartinib for epidermal growth factor receptor mutated non-small cell lung cancer: study protocol for a prospective, multicenter, open-label. Medicine (Baltimore). 2021;100(21):e25992. doi: 10.1097/MD.0000000000025992

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.