Abstract Multiple myeloma (MM) is a clonal malignancy of plasma cells accumulating in the bone marrow. MM cells are highly dependent on the bone marrow (BM) microenvironment for growth and survival through interactions particularly with BM stromal cells (BMSCs), which secrete important MM growth factors and cytokines. Understanding and defining these BM factors are critical to provide the rationale to functionally target these factors and/or kinases as novel biologically based therapeutics for MM. Bruton tyrosine kinase (Btk), a non-receptor tyrosine kinase resembling the Src family, plays a key role in the development and function of normal B cells through activation of the B-cell antigen receptor signaling pathway on binding to antigens. Btk further phosphorylates PLC-γ, leading to activation of MAPK, NF-κB, and AKT signaling pathways. Earlier our group synthesized a novel series of 5,7-dibromoisatin analogs. Analogs 6, 11 and 13 were potential anti-cancer agents. In the present study, through docking studies we predicted that bromo isatin analog-11 directly interacts with Btk. We found that Isatin-11 inhibits Btk activity in a dose- and time-dependent manner. Isatin-11 down-regulates the expression of Bcl-2, Bcl-xL on MM cells. Isatin-11 also activates caspase-3 and PARP-cleavage in MM cells. Taken together, these results suggest that targeting of Btk by Isatin-11 may represent a new therapeutic strategy to treat MM. Citation Format: Krishne Gowda, Manoj K. Pandey, Arun K. Sharma, Shantu Amin. Isatin analog as bruton tyrosine kinase inhibitor: A promising novel agent for multiple myeloma treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4204. doi:10.1158/1538-7445.AM2014-4204