Abstract 4068: HH-002, a derivative of Homoharringtonine, show promsing in diverse cancer models in preclinical characterization

Abstract

Abstract Homoharringtonine (HHT) is an anti-cancer drug used to treat imatinib resistant CML, and a reversible inhibitor of translation acting upon the early steps in polypeptide chain elongation. BS-HH-002.SA is a derivative of HHT. BS-HH-002.SA was shown to decrease the phosphorylation of Janus protein tyrosine kinase 2 (JAK2) as well as downstream targets, such as signal transducers and activators of transcription 3 and 5 (STAT3 and STAT 5), it also reduced Myeloid cell leukemia-1 (Mcl-1) protein level significantly and resulted in apoptosis. Evaluation of BS-HH-002.SA efficacy. was test in HEL, an erthroleukemia cell line carrying a JAK2V617F mutation which is seen in 90% of patients with polycythemia vera (PCV) and half of those with essential thrombocythemia or primary myelofibrosis. HH-002.SA showed was highly potent (at low nM concentration) to HEL. Efficacy of BS-HH-002 was tested in a recombinant human erythropoietin injection (rhEpo)-induced murine model of polycythemia Vera, Treatment with BS-HH-002.SA BID for 4 days showed a significant inhibitory effect on rhEpo induced increase in reticulocytes, hematocrit and splenomegaly, as well as in red blood cell, white blood cell and platelet counts. Furthermore, histology evaluations revealed that BS-HH-002.SA exerted an inhibitory effect on rhEpo induced extramedullary hematopoiesis in spleen, and decreased cellularity in bone marrow with more predominant effect on erythroid cells than on myeloid cells. Also, BS-HH-002.SA also show potent in vitro and in vivo efficacy in pancreatic cancer cell line KP-4 and non-small cell lung cancer (NSCLC) NCI-H1975, BS-HH-002.S inhibited STAT3 Tyrosine 705 phosphorylation and reduced anti-apoptotic proteins expression Mcl-1 protein levels in both two cancer cell lines. Note: This abstract was not presented at the meeting. Citation Format: Hank Rui. HH-002, a derivative of Homoharringtonine, show promsing in diverse cancer models in preclinical characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4068. doi:10.1158/1538-7445.AM2017-4068