Completed R&D programs

EZH2 inhibitors

BRAF inhibitors

MEK1 inhibitors

BTK inhibitors

EZH2 is a histone methyltransferase that catalyzes the methylation of histone3 lysine 27 (H3K27), playing an important role in stem cell pluripotency and germline development. EZH2 gain-of-function mutations at Y641 occur in 22% of germinal center B cell diffuse large B cell lymphoma (GCB-DLBCL) and 7-12% of follicular lymphoma (FL), contributing to the development and progression of B-cell lymphomas. Moreover, dysregulation of EZH2 activity plays an oncogenic role in a set of genetically defined solid tumors that include malignant rhabdoid tumors, synovial sarcomas and ovarian cancers.

As part of our on-going effort in oncology research, we have discovered novel, potent, and selective EZH2 inhibitors. Our lead compound EBI-2554 exhibited superior in vitro potency and in vivo efficacy in Pfeiffer xenograft mouse model, leading to durable and complete tumor regression at certain dose levels. No evidence of overt toxicities was observed in a 7-day mouse toxicity study, with an excellent therapeutic window. We are currently performing IND enabling studies and pursuing partnership opportunities for clinical development of this compound in the global market.

The oncogenic mutation of BRAF^V600E has been found to be a critical driver of uncontrolled cell proliferation in 8% of all human cancers, including more than 60% of melanoma, 45% of papillary thyroid cancer and 10% of colorectal cancer. It is one of the best validated drug targets for targeted cancer therapy and BRAF-specific small molecule inhibitors such as Vemurafenib and Dabrafenib have shown efficacy in clinical settings. We have discovered novel, potent, and selective BRAF^V600E inhibitors through structure-guided approach. Our lead compounds, EBI-907 and -945, exhibited superior in vitro potency and in vivo efficacy when compared with Vemurafenib or Dabrafenib. The compounds also benchmarked favorably in a variety of pharmaceutical profilings including CYP450 and hERG inhibition. No evidence of epithelial hyperplasia and other toxicities were observed in rodent and canines with prolonged oral administration and sustained exposure. We are pursuing partnership opportunities for this program.

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) is an important serine/threonine kinase in the RAS/RAF/MEK/ERK pathway that controls mammalian cell proliferation, survival, differentiation and migration. Oncogenic mutations frequently occur in this pathway and cause many human cancers including melanomas, pancreatic, colorectal, ovarian and lung cancers. Inhibitors of MEK including GSK1120212, AZD6244, and PD0325901 have demonstrated efficacy against malignant tumors characterized by mutations in either RAS or Raf in both preclinical and clinical settings, especially in combo-therapy with BRAF or other kinase inhibitors. We have developed novel, potent, and selective inhibitors of MEK1 through structure-based approach. Our lead compound EBI-1051 showed superior in vivo efficacy and safety in preclinical models. This compound is now undergoing clinical trials in China.

Bruton’s tyrosine kinase (BTK) is an essential component of the B-cell receptor (BCR) signaling pathways that regulate the survival, activation, proliferation, and differentiation of B lymphocytes. Targeting BTK with small molecule inhibitors has been demonstrated to be an effective treatment option for B-cell lymphomas and autoimmune diseases. The first BTK inhibitor, Ibrutinib, jointly developed by Pharmacyclics and Johnson & Johnson, was approved by FDA for the treatment of Mantle cell lymphoma and chronic lymphocytic leukemia. We have discovered two structurally distinct, pharmacologically potent and selective BTK inhibitors, EBI-1266 and -1459, through structure-guided approach. When compared to Ibrutinib, our compounds are at least equally potent in vitro toward BTK with either a better selectivity profile or much better in vivo exposure, leading to two clinical candidates showing significantly better in vivo efficacy and broader safety margins in preclinical studies. EBI-1459/1266 (now SHR-1459/1266) are undergoing clinical trials in Asia and licensed to TG Therapeutics for global clinical trials outside Asia (but including Japan).