Hauv phau ntawv keeb kwm ntawm kev kho mob qog noj ntshav, tshuaj tiv thaiv ib txwm yog Damocles rab ntaj dai ntawm cov kws kho mob taub hau. Kev tshwm sim ntawm trastuzumab tau muab suav tsis txheeb HER2- cov neeg mob qog noj ntshav zoo cia siab, tab sis qhov feem tseem ceeb ntawm qhov kawg tau ntsib cov tshuaj tiv thaiv thiab rov qab los. Tsuas yog thaum tej yam zoo li tsis muaj kev cia siab, ib qho tshuaj me me hu ua Lapatinib Ditosylate Powder muaj qhov ci ntsa iab ntawm kev cia siab.
Lapatinib Ditosylate hmoov(CAS 388082-78-8), ua lag luam li Tykerb, yog lub qhov ncauj me me-molecule tyrosine kinase inhibitor tsim los ntawm GlaxoSmithKline. Nws qhov sib txawv loj tshaj plaws los ntawm trastuzumab yog qhov tom kawg yog ib qho loj-molecule monoclonal antibody uas tuaj yeem khi rau lub extracellular domain ntawm HER2 receptor; thaum Lapatinib Ditosylate yog ib qho me me molecule uas tuaj yeem nkag mus rau hauv cov cell membrane, zoo thaiv cov qog nqaij hlav qog nqaij hlav hauv lub cev.
Cov qauv molecular-lub tswv yim ntsev thiab "dual-lub hom phiaj" lub hauv paus
Lapatinib Ditosylate tus niam txiv tub ntxhais yog 4-phenylaminoquinazoline, ib tug raug hydrophobic skeleton. Raws li tuaj yeem pom los ntawm nws cov mis molecular C₂₉H₂₆ClFN₄O₄S, nws muaj ntau lub nplhaib uas muaj ntxhiab, thaum nws pawg hydrophilic muaj tsuas yog sulfonylethylamine sab saw. Qhov no ua rau muaj tus nqi LogP siab thiab tsis muaj dej solubility. Raws li cov khoom siv raw khoom, qhov siab tshaj plaws solubility ntawm cov dawb lapatinib puag hauv dej tsuas yog nyob rau hauv 1-10 μM ntau yam. Qhov no txhais tau hais tias yog lub hauv paus dawb tau noj ncaj qha, cov tshuaj yuav ua rau hauv lub plab zom mov, ua rau nws nyuaj rau hla txoj hnyuv epithelial barrier thiab nkag mus rau hauv cov hlab ntsha.
Lapatinib Ditosylate muaj cov qauv molecular C₂₉H₂₆ClFN₄O₄S·2C₇H₈O₃S, nrog rau qhov hnyav molecular ntawm 925.46 Da. Lub "Ditosylate" hauv nws lub npe qhia tias txhua lub molecule ntawm Lapatinib Ditosylate puag yog khi rau ob lub molecules ntawm p-toluenesulfonic acid. Vim li cas ob lub molecules? Nitrogen atom ntawm N-3 txoj hauj lwm ntawm quinazoline nplhaib nyob rau hauv lubLapatinib Ditosylatemolecule muaj lub hauv paus tseem ceeb, ua rau nws tsim ib daim ntawv cog lus ionic nrog sulfonic acid pawg p-toluenesulfonic acid. Nyob rau tib lub sijhawm, lwm qhov chaw hauv cov molecule kuj tseem tuaj yeem koom nrog hauv protonation, tswj kev ruaj khov stoichiometric piv ntawm 1: 2.
Qhov zoo ntawm daim ntawv ntsev no yog qhov tseem ceeb:
- Solubility nce ntxiv: Tom qab tsim ntsev, cov tshuaj yaj sai sai hauv dej, tso lub hauv paus rau qhov ncauj nqus.
- Txhim khu kev ruaj ntseg: Crystalline p-toluenesulfonate muaj qhov dej zoo- cov ntsiab lus melting thiab cov tshuaj lom neeg ruaj khov, ua kom yooj yim rau ntev - lub sij hawm cia thiab kev tsim tawm.
- Monohydrate daim ntawv: Cov khoom lag luam muaj cov khoom xyaw tshuaj nquag muaj nyob hauv daim ntawv monohydrate, nrog rau qhov hnyav ntawm kwv yees li 943.48 Da. Lub xub ntiag ntawm dej molecules ntxiv stabilizes crystal lattice qauv.
Tshaj li cov ntsev ntsev, lub cev nqaij daim tawv pharmacodynamic ntawm Lapatinib Ditosylate yog nws tus kheej ua haujlwm ntawm kev kos duab. Raws li cov qauv- kev sib raug zoo ntawm kev sib raug zoo los ntawm Wood et al. Los ntawm crystallography, lapatinib yog qhov tshwj xeeb hauv qhov nws nyiam khi rau qhov tsis ua haujlwm ntawm EGFR.
Nyob rau hauv lub xeev tsis muaj zog ntawm EGFR, C-helix hauv ATP- khi hnab tshos tau txais kev sib hloov thiab kev txhais lus, tsim kom muaj kab noj hniav dav dua. Cov pawg loj 3-fluorobenzyloxy nyob rau hauv Lapatinib Ditosylate molecule tuaj yeem haum rau hauv cov kab noj hniav no, tsim kom muaj kev sib cuam tshuam hydrophobic ruaj khov. Ib txhij, pawg N-1 ntawm lub nplhaib quinazoline tsim ib qho tseem ceeb hydrogen daim ntawv cog lus nrog Met793 residue ntawm EGFR, thaum pawg methanesulfonyl ethylamine nyob rau sab saw txuas mus rau thaj tsam hnyav, tswj tag nrho cov solubility ntawm cov molecule.
Los ntawm mob qog noj ntshav mis mus rau kev kho mob ntawm ntau hom qog
Nws daim ntawv thov tseem ceeb tsom mus rau HER2-overexpressing cov qog nqaij hlav, feem ntau mob qog noj ntshav, tab sis kuj txuas mus rau lwm qhov chaw xws li mob plab thiab mob ntsws. Nws ua tiav kev tswj cov qog nqaij hlav los ntawm kev kho mob monotherapy lossis kev kho ua ke, txhawb nqa los ntawm cov ntaub ntawv kho mob meej.
Tom qab- kab kev kho mob: Rau HER2- qhov zoo tshaj plaws / metastatic mis mob qog noj ntshav uas tau ua tsis tiav anthracyclines, paclitaxel, lossis trastuzumab, Phase III kev soj ntsuam kuaj EGF100151 pom tias qhov nruab nrab tsis muaj kev vam meej nyob rau hauv kev sib xyaw nrog kev kho mob nrog capecitabine.6 lub lis piam zoo dua li ntawm 2 lub lis piam. capecitabine monotherapy pab pawg; Lub hom phiaj teb tus nqi yog 23.7%, piv rau tsuas yog 13.9% rau kev kho mob monotherapy. Ntawm cov neeg koom, 97% muaj theem IV mob qog noj ntshav mis, thiab 95% yog HER2 IHC 3+ lossis IHC 2+ thiab FISH zoo, lees paub nws cov txiaj ntsig hauv cov neeg mob tiv taus trastuzumab.
Ua ntej- kab kev sib xyaw ua ke: Rau HER2- qhov zoo, cov tshuaj hormones receptor-positive postmenopausal metastatic cancer mis, cov txiaj ntsig kev kho mob ntawm kev sib xyaw ua ke nrog cov tshuaj letrozole tau ntau dua li cov pab pawg monotherapy, muaj txiaj ntsig ncua kev kho endocrine tsis kam thiab ua kom tsis muaj sia nyob ntev.
Kev kho mob hlwb metastasis: Kev sim tshuaj ntsuam xyuas CEREBREL pom tias nws tuaj yeem nkag mus rau hauv cov ntshav -b hlwb barrier thiab inhibit HER2-zoo mob qog noj ntshav hauv lub hlwb hlwb metastases, txo qhov kev pheej hmoo ntawm kev mob plawv hauv nruab nrab.
Hauv kev sim hauv vitro,Lapatinib Ditosylatepom tau hais tias muaj zog inhibitory cuam tshuam rau cell proliferation. Rau HER2- overexpressing mis mob qog noj ntshav kab BT474 thiab SKBr3, nws ib nrab - qhov siab tshaj plaws inhibitory concentrations (IC50) tsuas yog 25 nM thiab 32 nM, feem. Txawm li cas los xij, rau cov kab xov tooj ntawm tes uas tsis tshua muaj EGFR thiab HER2 qhia, IC50 tau nce mus rau qib micromolar, ua kom pom nws qhov kev xaiv.Nyob rau theem pivotal III kev soj ntsuam, Lapatinib Ditosylate nrog capecitabine ua rau lub sijhawm nruab nrab ntawm kev nce qib -dawb ciaj sia taus piv rau capecitabine ib leeg. Txawm hais tias qhov tshwm sim ntawm qhov tsis zoo tshwm sim xws li zawv plab, pob khaus, thiab tes-ko taw syndrome yog qhov siab, tag nrho kev zam tau raug tswj tau.
Lapatinib Ditosylate lub peev xwm txuas ntxiv dhau ntawm lub mis mob cancer. Ib txoj kev tshawb fawb 2017 los ntawm Bai et al. tshawb nrhiav nws daim ntawv thov hauv HER2-positive gastric cancer. Lawv pom tias ua kom cov Chk1 kinase hauv cov qog nqaij hlav hauv plab txo qis Lapatinib Ditosylate rhiab heev, qhia tias kev sib txuas nrog Chk1 inhibitor yuav yog lub tswv yim los kov yeej kev tiv thaiv. Qhov kev tshawb pom no nthuav dav Lapatinib Ditosylate kev tshawb fawb los ntawm mob qog noj ntshav ntawm lub mis mus rau ntau yam ntawm HER2-tsav cov qog nqaij hlav.
Ib dual -receptor blocking signal "braking system"
Tib neeg epidermal growth factor receptor (EGFR) tsev neeg muaj plaub tug tswv cuab: EGFR/HER1, HER2, HER3, thiab HER4. Hauv cov cell qub, lawv tswj kev loj hlob, kev sib txawv, thiab kev ciaj sia. Txawm li cas los xij, hauv cov qog nqaij hlav cancer, HER2 gene amplification ua rau receptor overexpression, thiab txawm tias tsis muaj kev loj hlob sab nraud, receptors spontaneously tsim dimers thiab ua kom qhib tau.
Cov txiaj ntsig ntawm kev ua kom muaj zog: Tom qab HER2 thiab HER3 daim ntawv heterodimers, lub intracellular tyrosine kinase domain yog qhib, hloov cov phosphate pawg ntawm ATP rau nws tus kheej los yog downstream protein's tyrosine residue. Qhov kev tshwm sim phosphorylation no, zoo li cov nyhuv domino, ua rau ob txoj hauv kev tseem ceeb ntawm oncogenic: RAS-RAF-MEK- ERK txoj hauv kev, uas tswj cov cell proliferation, thiab PI3K-AKT-mTOR txoj hauv kev, uas tswj cov cell survival{9}, metabolism.
Lapatinib Ditosylateyog ib qho kev thim rov qab ATP -kev sib tw tyrosine kinase inhibitor. Nws "sib tw" nrog ATP- khi rau nws ua ntej nws tuaj yeem nkag mus rau receptor's ATP- khi hnab ris, yog li thaiv cov phosphorylation.
Qhov tshwj xeeb tus nqi ntawm nws dual - lub hom phiaj mus kom ze: Feem ntau HER2- cov tshuaj tiv thaiv tsuas yog inhibit HER2 xwb, tab sis Lapatinib Ditosylate inhibits EGFR thiab HER2. Vim li cas qhov no tseem ceeb? Vim hais tias thaum HER2 yog inhibited, cov qog nqaij hlav cancer tuaj yeem kho EGFR raws li "thaum" los tswj cov teeb liab hloov. Lapatinib lub hom phiaj ob lub hom phiaj tag nrho thaiv txoj kev khiav tawm no.
Thaum Lapatinib Ditosylate blocks receptor phosphorylation, downstream ERK thiab AKT kinases kuj "kaw." Cov txiaj ntsig yog:
- Cell voj voog raug ntes: Cyclin D protein ntau txo qis, thiab cov hlwb raug ntes nyob rau theem G1.
- Apoptosis induction: Hauv qee cov kab ntawm tes, Lapatinib Ditosylate tuaj yeem txhim kho kev ua tau zoo los ntawm kev ua kom autophagic cell tuag.
- Reversal of resistance: Lapatinib Ditosylate tseem zoo tiv thaiv trastuzumab -cov qog cell kab mob vim nws qhov chaw ua haujlwm (intracellular kinase domain) txawv ntawm trastuzumab's (extracellular domain).
Raws li kev noj tshuaj hauv qhov ncauj, Lapatinib Ditosylate's bioavailability nws txawv ntawm ib tus neeg mus rau lwm tus thiab cuam tshuam los ntawm cov khoom noj. High- noj zaub mov muaj roj ntau tuaj yeem ua rau nws nqus tau zoo; Yog li ntawd, kev kho mob feem ntau pom zoo kom noj nws 1 teev ua ntej lossis tom qab noj mov kom tswj tau cov ntshav kom ruaj khov.
Lapatinib Ditosylatefeem ntau metabolized los ntawm kab mob siab CYP3A4 thiab CYP3A5; Yog li ntawd, kev kho koob tshuaj yog tsim nyog thaum siv concomitantly nrog CYP3A4 inducers los yog inhibitors. Nws ib nrab -lub neej yog kwv yees li 24 teev, txhawb nqa ib zaug - noj txhua hnub. koob tshuaj- txwv tsis pub muaj tshuaj lom muaj xws li raws plab thiab hepatotoxicity, yuav tsum tau saib xyuas lub siab ua haujlwm tsis tu ncua.
Kev tawg los ntawm ntau npaum li cas daim ntawv optimization mus rau kev kho ua ke
Kev lig kev cai Lapatinib Ditosylate synthesis suav nrog ntau cov kuab tshuaj organic, uas tsis yog tsuas yog ib puag ncig tsis zoo, tab sis kuj ua rau cov nqi tsim khoom thiab kev nyab xeeb. Xyoo 2025, Sompura et al. luam tawm ib qho kev tshawb fawb loj hauv * Phau ntawv Journal ntawm Molecular Structure *, tsim ib txoj kev ntsuab hluavtaws siv cov dej thiab cov dej rov ua dua tshiab ua cov tshuaj tiv thaiv thawj zaug.
Lapatinib Ditosylate's BCS Class II cov khoom tau yog ib qho kev sib tw loj hauv kev tsim kho. Hu et al. tshawb xyuas qhov kev npaj ntawm Lapatinib Ditosylate khoom dispersions siv cov kuab tshuaj rotary evaporation thiab kub- cov txheej txheem yaj extrusion los txhim kho nws cov kev sib cais.
Kev tshawb fawb ntxiv yog Singh li al., uas tau tsim ib daim ntawv lipophilic ntsev ntawm Lapatinib Ditosylate los txhim kho nws lipophilicity, ua rau nws haum rau lipid- raws li formulations. Cov tswv yim no tsis yog tsuas yog ua kom cov tshuaj thauj khoom tab sis kuj tseem tuaj yeem ua rau lymphatic - lub hom phiaj xa khoom, hla ua ntej - dhau cov metabolism hauv lub siab.
Raws li tau hais ua ntej, qhov tshiab dimeric impurity txheeb xyuas los ntawm Yerla li al. xyoo 2025 sawv cev rau kev lag luam kws tshuaj txuas ntxiv nce kev thov rau API zoo. Nrog rau kev siv dav dav ntawm ultra-kev ua haujlwm siab ua kua chromatography- siab daws teeb meem loj spectrometry thiab ob-dimensional nuclear magnetic resonance (NMR) technologies, ntau dua yav dhau los "tsis pom" kab impurities tau tshwm sim. Qhov no yog ib qho tseem ceeb heev rau cov tuam txhab tshuaj generic-lawv yuav tsum ua kom pom tias lawv cov khoom zoo ib yam nrog cov tshuaj qub hauv cov ntsiab lus ntawm impurity profiles.
Xaus
Lapatinib Ditosylate Powder, nrog rau nws cov txheej txheem tseem ceeb ntawm "qhib dual- lub hom phiaj thaiv," tau dhau los ua cov cuab yeej tseem ceeb rau kev kho HER2-zoo qog. Los ntawm mob qog noj ntshav rau ntau hom qog nqaij hlav, los ntawm kev kho mob monotherapy mus rau kev sib xyaw ua ke, nws tau ua tiav kev soj ntsuam, ua kom pom tseeb meej thiab kev nyab xeeb. Tam sim no, los ntawm ntau npaum li cas daim ntawv optimization, kev sib xyaw ua ke, thiab kev tshawb fawb mechanism, nws daim ntawv thov ciam teb txuas ntxiv, thiab nws yuav tsum ua lub luag haujlwm tseem ceeb hauv kev kho mob oncology yav tom ntej. Raws li cov khoom siv tshuaj raw khoom, kev tswj xyuas meej ntawm nws cov qauv thiab kev ua haujlwm, nrog rau kev tsim kho tshiab hauv kev siv tshuaj thiab cov txheej txheem, yog qhov tseem ceeb rau kev ua kom muaj txiaj ntsig zoo thiab muab kev taw qhia rau kev tshawb fawb thiab kev loj hlob yav tom ntej.
Xi'an Faithful BioTech Co., Ltd. muab siab - zooLapatinib Ditosylate hmoovnrog purity txog li 99%. Yog xav paub ntxiv, thov emailallen@faithfulbio.com.
Cov ntaub ntawv
- Meilunbio. (nd). Lapatinib Ditosylate: Khoom specification
- ChemSpider. (nd). Lapatinib ditosylate. Royal Society of Chemistry.
- National Cancer Institute. (2002). Lapatinib Ditosylate. NCI Metathesaurus.
- Yerla, RR, Babu, MSS, Saravanakumar, M., Chormale, S., Krishnamurthy, KS, & Sunitha, K. (2025). Kev rho tawm, kev ua tus cwj pwm, thiab kev ntsuam xyuas tus qauv ntawm Novel Isomeric Dimer Impurities nrhiav tau thaum lub sij hawm tsim Lapatinib Ditosylate siv Preparative HPLC, HRMS, thiab NMR Techniques. Separation Science Plus, 8, e70101.
- Stanford University. (2013). Lapatinib Ditosylate thiab Radiation Therapy hauv Kev Kho Mob Cov Neeg Mob Nrog Kev Kho Mob Hauv Zos Advanced lossis Locally Recurrent Breast Cancer (NCT01868503). ClinicalTrials.gov.
- NCATS Inxight Drugs. (nd). Lapatinib Ditosylate. National Center rau Advancing Translational Sciences.