Merck's thawj ATR Tus Neeg Saib Xyuas Berzosertib + Topotecan Cov Lus Qhia-ntawm-lub tswvyim Theem 2 Kev Qhia Ua Kom Tau Muaj Zog!

Merck (Merck KGaA)' s kev saib xyuas kev lag luam kev lag luam kho mob Merck Serono (EMD Serono) tsis ntev los no tau tshaj tawm cov kev kho mob tseem ceeb ntawm cov tshuaj tua kab mob tshuaj tua kab mob berzosertib (M6620), uas yog thawj-hauv chav kawm, muaj peev xwm, xaiv ataxia telangiectasia thiab Rad3-cuam tshuam cov protein (ATR) inhibitor, ATR yog lub ntsiab kev ua haujlwm ntawm kev teb rov qab txog kev ntxhov siab. Berzosertib tuaj yeem thaiv ATR cov haujlwm hauv qog nqaij hlav cancer los tiv thaiv qog hlwb los kho kev puas tsuaj los ntawm kev kho DNA, ua rau kev mob qog nqaij hlav hauv lub cev tuag, kev mob qog rov qab, thiab ua kom zoo dua ntawm kev kho mob.

Berzosertib, yav dhau los hu ua VX-970, tau kev tso cai los ntawm Merck los ntawm Vertex Pharmaceuticals hauv 2017. Cov tshuaj no yog qhov khoom tseem ceeb ntawm Merck cov DNA puas teb (DDR) qhov kev tiv thaiv qhov project thiab ib qho ntawm feem ntau tshaj ATR inhibitors hauv kev kho mob ntawm oncology hauv kev lag luam. Ib tug. Raws li ib feem ntawm DDRiver cov chaw kuaj mob tshiab, Merck tabtom tshawb xyuas DDR inhibitor tsom cov phiajcim cov kab mob hauv ntau dua 10 kev kuaj mob rau ntau hom qog.

Kev siv tshuaj kho mob rhuav cov DNA ntawm cov qog nqaij hlav cancer, ua rau cov cell tuag, thiab ua kom cov qog. Tab sis sijhawm dhau sijhawm, kev siv tshuaj kho mob yuav plam qee tus neeg mob. Qhov no yog ib nrab vim yog qhov ua tau zoo DNA kev kho kev puas tsuaj siv los ntawm cov qog hlwb. Los ntawm kev tshuaj ntsuam cov tshuaj lom neeg, cov kws tshawb nrhiav tau pom tias qhov inhibition ntawm ATR (tus neeg ua haujlwm loj ntawm kev rov ua kev ntxhov siab) thiab qhov inhibition ntawm topoisomerase I (TOP1, ribozyme uas inhibits genome instability) pom muaj nyob hauv cov leeg mob ntsws me me (SCLC). Synergistic cytotoxicity.

Molecular qauv ntawm berzosertib (duab los ntawm: medchemexpress.com)

Raws li cov lus tshaj tawm, kev soj ntsuam ntawm theem II pov thawj-ntawm-kev tshawb pom (NCT02487095) nqa los ntawm National Cancer Institute (NCI) thiab luam tawm nyob rau hauv kev kho mob thoob ntiaj teb phau ntawv Cancer Cancer (NCT02487095) tau lees tias berzosertib (ATR inhibition) Tshuaj ) ua ke nrog kev siv tshuaj kho mob topotecan (TOP1 inhibitor) hauv kev kho mob rau cov neeg mob uas muaj cov kab mob ntsws me me hauv lub ntsws (SCLC) muaj cov nyhuv tseem ceeb, nrog lub hom phiaj teb cov lus teb (ORR) ntawm 36% (n=9/25), mus txog rau thawj qhov cov txiaj ntsig ntawm qhov kawg. Tshwj xeeb, ntawm cov neeg mob platinum-resistant nyob rau hauv kev zam txim, feem ntau cov neeg mob qhia qhov kev zam ntev ntev, thaum cov neeg mob platinum-resistant feem ntau tuag nyob hauv ob peb lub lis piam rov mob.

Topotecan yog ib qho TOP1 inhibitor, kev kho mob rau cov tshuaj tua kab mob rau txoj kev kho thib ob ntawm cov kab mob ntsws me me, thiab cuam tshuam nrog tus nqi lus teb tsawg, tshwj xeeb tshaj yog cov kab mob platinum-resistant. Cov kev tshawb pom los ntawm NCI txoj kev tshawb pom tseem ceeb txog qhov tsis muaj zog ntawm SCLC qog rau ATR inhibition vim tias muaj kev ntxhov siab ntau ntxiv, nrog rau lub peev xwm ntawm berzosertib thiab topotecan txhawm rau txhim kho kev ua tau zoo ntawm topotecan hauv cov neeg siv tshuaj kho mob. Cov ntaub ntawv no yog saib raws cov txiaj ntsig ib theem Kuv kawm luam tawm ua ntej dhau los ntawm cov ntaub ntawv pov thawj tshawb fawb no, thiab cov txiaj ntsig no tseem qhia tau tias kev sib xyaw ntawm berzosertib thiab topotecan muaj txiaj ntsig zoo rau platinum-resistant SCLC cov neeg mob.

NCI tseem tab tom ua lwm qhov kev sim qib II (NCT03896503) txhawm rau ntsuas cov tshuaj sib xyaw ua ke ntawm berzosertib + topotecan thiab ib leeg-tus neeg sawv cev kiag ntawm topotecan rau kev kho mob rov muaj mob me me ntawm cov ntsws mob ntsws. Qhov no tam sim no tsuas yog tib qho kev ua tiav hauv cov neeg mob no. Kev tswj xyuas kev sib tw ntawm cov tshuaj sib txuam. Ntxiv rau, Merck Serono kuj tau pib lub ntiaj teb, qhib-daim ntawv lo, tib txhais tes Ntu II kawm (DDRiver SCLC 250) txhawm rau soj ntsuam ntxiv qhov kev ua tau zoo ntawm berzosertib + topotecan hauv kev kho mob rov ua dua tshiab platinum-resistant me cell mob ntsws. , thawj rooj plaub Tus neeg mob tau suav nrog hauv kev sim. Lub phiaj xwm sim muaj xws li ntawm 80 tus neeg mob hauv thaj tsam 41 qhov chaw kawm hauv Asia, Europe thiab North America.

Cov txiaj ntsig no yog ntxiv rau cov txiaj ntsig ntawm qhib-daim ntawv lo, sib tw, ntu II kev kawm (NCI raws li kev cai 9944) kev txhawb nqa los ntawm NCI, uas tau soj ntsuam cov kev ua tau zoo ntawm berzosertib hauv kev sib xyaw nrog gemcitabine thiab gemcitabine ib leeg hauv kev kho mob ntawm rov mob, platinum-resistant. high-qib serous ovarian mob cancer. Cov txiaj ntsig ntawm qhov kev tshawb fawb tau tshaj tawm hauv The Lancet Oncology hauv 2020. Qhov kev tshawb fawb no tau ua los ntawm kev sib koom tes tshawb fawb txog kev sib koom tes thiab kev tsim kho tshiab (CRADA) cov lus pom zoo ntawm NCI thiab Merck. Nws yog thawj zaug kev kawm txog random ntawm ATR inhibitors rau ib hom qog. Cov txiaj ntsig tau qhia tias hauv qhov kev kho mob no ib puag ncig, ntxiv ntawm berzosertib rau gemcitabine muaj Kev Pab Kho Mob muaj xws li txhim kho kev vam meej-tsis muaj sia nyob (PFS).

Tus thawj coj tshawb fawb ntawm NCI pov thawj-ntawm-tswvyim II kev kawm thiab NCI tus kws tshawb fawb Anish Thomas, MD, tau hais tias:" Kab mob khees-xaws me me ntawm cov leeg mob hlwb (SCNC), suav nrog kev mob ntsws me me hauv lub ntsws (SCLC), muaj qhov tsis raug mob tsis zoo thiab yog loj soj ntsuam kev sib tw. Hauv txoj kev tshawb fawb no, kev sib koom ua ke ntawm kev kho berzosertib thiab topotecan qhia tau pom qhov siab dua-kev cia siab txog kev kho mob thiab kev kho mob ntev kawg hauv platinum-resistant SCLC cov neeg mob, qhia txog cov txiaj ntsig ntawm kev sib xyaw ua ke no rau cov neeg mob uas muaj hom kabmob refractory muaj peev xwm kho tau."

Danny Bar-Zohar, Tus Thawj Coj Thoob Ntiaj Teb ntawm Merck Serono, tau hais tias:" Peb raug txhawb los ntawm cov txiaj ntsig tau zoo no. Raws li ib feem ntawm peb txoj haujlwm ua thawj zaug hauv DNA kev tshawb fawb txog kev puas tsuaj, peb mob siab yuav los ua cov kauj ruam txuas ntxiv hauv qhov kev sim rau npe rau kev kho mob ntawm SCLC. Kawm berzosertib."