Abstract 2597: BGB-3111 is a novel and highly …

1 Abstract 2597: BGB-3111 is a novel and highly selective Bruton's tyrosine kinase (BTK) [2015/11/6 10:57:43]Current IssueNovember 1, 2015, 75 (21)Alert me to new issues ofCancer Research+ Abstract 2597: BGB-3111 is a novel andhighly selective Bruton's tyrosine kinase (BTK)inhibitorNa Li, Zhijian Sun, Ye Liu, Mingming Guo, Yilu Zhang, Dongping Zhou, Bo Zhang,Dan Su, Shuo Zhang, Jing Han, Yajuan Gao, Yunhang Guo, Zhiwei Wang,Min Wei, Lusong Luo, and Lai WangAuthor AffiliationsProceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAAbstractBTK, an essential component of the BCR pathway, has emerged as novel target in thetreatment of B-cell malignancies.

2 Although Ibrutinib, the first-in-class irreversibleinhibitor of BTK, showed promising clinical activity, recent study revealed that ibrutinibcould antagonize rituximab induced antigen-dependent cell-mediated cytotoxicity(ADCC) by inhibiting ITK kinase activity (Kohrt et. al., 2013), suggesting the potentiallimitations in its clinical application. BGB-3111 is a novel , highly selective , secondgeneration BTK inhibitor, currently under clinical investigation in hematological biochemical, cellular and in vivo activities were reported in this both biochemical and cellular assays, BGB-3111 demonstrated nanomolar BTKinhibition activity.

3 In several MCL and DLBCL cell lines, BGB-3111 inhibited BCRaggregation-triggered BTK autophosphorylation, blocked downstream PLC- 2 signaling,and potently inhibited cell proliferation. In comparison with ibrutinib, BGB-3111 showedmuch more restricted off-target activities against a panel of kinases, including ITK. Whileibrutinib significantly inhibited rituximab-induced NK cell IFN- secretion and in vitrocytotoxicity on mantle cell lymphoma cells, BGB-3111 was at least 10-fold weaker thanibrutinib in inhibiting rituximab induced ADCC, consistent with its weak ITK mouse BTK occupancy assays, treatment with BGB-3111 resulted in a dose-dependent BTK occupancy and showed about 3-fold more potency than ibrutinib intarget organs, including PBMC and spleen.

4 BGB-3111 induced dose-dependent anti-tumor effects against REC-1 MCL xenografts engrafted either subcutaneously orsystemically via tail vein injection in mice. In the subcutaneous xenografts, BGB-3111 mg/kg BID showed similar activity as ibrutinib at 50 mg/kg QD, its clinical relevantdose. In the systemic model, the median survival of BGB-3111 25 mg/kg BID groupwas significantly longer than those of both ibrutinib 50 mg/kg QD and BID groups. In anABC-subtype DLBCL (TMD-8) subcutaneous xenograft model, BGB-3111 alsodemonstrated better anti-tumor activity than ibrutinib.

5 Preliminary 14-day toxicity studyin rats showed that BGB-3111 was very well tolerated and maximal tolerate dose (MTD)was not reached when it was dosed up to 250mg/ conclusion, BGB-3111 is a highly selective and potent BTK inhibitor. It does notaffect rituximab-induced ADCC and demonstrated better efficacy than ibrutinib in--+++ Previous | Next Article Table of ContentsThis Articledoi: Res August 1, 2015 75;2597 Meeting AbstractClassificationsExperimental and MolecularTherapeuticsPoster Presentations -Proffered AbstractsPoster Presentations- MAPK, EGFR, andBTK InhibitorsServicesEmail this article to a colleagueAlert me when this article iscitedAlert me if a correction ispostedSimilar articles in this journalDownload to citation managerGoogle ScholarPubMedSocial Bookmarking Home OnlineFirst Current Issue Past Issues Subscriptions Alerts Feedback AACR Publications CME AACR HomeUser NamePassword Advertisement:: AACR Publications Home.

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7 Correction: Host ImmuneDefense Peptide LL-37 Activates Caspase-Independent Apoptosis andSuppresses Colon Cancer2. Mapping the Pathways ofResistance to TargetedTherapies3. Cell-of-Origin of Cancerversus Cancer Stem Cells:Assays and Interpretations4. Metastasis SuppressorsRegulate the TumorMicroenvironment byBlocking Recruitment ofPrometastatic Tumor-Associated Macrophages5. A Quantitative System forStudying Metastasis UsingTransparent Zebrafish View all Most Read articlesxenograft models, supporting further clinical investigation of this compound both assingle agent and in combination with anti-CD20 antibodies in hematological Format: Na Li, Zhijian Sun, Ye Liu, Mingming Guo, Yilu Zhang, DongpingZhou, Bo Zhang, Dan Su, Shuo Zhang, Jing Han, Yajuan Gao, Yunhang Guo, ZhiweiWang, Min Wei, Lusong Luo, Lai Wang.

8 BGB-3111 is a novel and highly selectiveBruton's tyrosine kinase (BTK) inhibitor. [ Abstract ]. In: Proceedings of the 106th AnnualMeeting of the American Association for Cancer Research; 2015 Apr 18-22;Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl): Abstract nr2597. 2015 American Association for Cancer Connotea Delicious Digg Facebook Google+ Reddit TwitterWhat's this?Clinical Cancer ResearchMolecular Cancer ResearchMolecular Cancer TherapeuticsAACR Publications CMEC ancer Prevention JournalsPortalCancer Reviews OnlineAnnual Meeting EducationBookMeeting AbstractsHel