BPI-9016M is an Orally Active and Selective Dual c-Met/AXL Inhibitor
Posted On 2020-03-05
c-Met is a membrane-spanning receptor tyrosine kinase. It has a high affinity for binding to hepatocyte growth factor (HGF).
As we all know, HGF/c-Met signaling often involves activation of its downstream pathways.
High-level Met gene amplification, mutation or protein overexpression can lead to aberrant activation of the HGF/c-Met pathway. In addition, this dysregulation often plays a role in tumor development and metastatic progression.
Lung cancer is a severely malignant form of human cancers. It is a leading cause of cancer death in many countries. 20–37% of tumor tissues exists Met protein overexpression, meanwhile, Met gene mutation is reported in 5–26% of NSCLC patients with EGFR inhibitor resistance.
AXL overexpression exists in 20% of NSCLC patients with resistance to EGFR inhibitors.
Additionally, AXL-targeting therapies are more and more prevalent in NSCLC patients bearing wild-type EGFR tumors.
Based on the above description, in this article, we will introduce a potent, orally active, and selective dual c-Met and AXL tyrosine kinases inhibitor, BPI-9016M.
We will describe its anti-cancer activity in vitro and in vivo.
Firstly, we can find that BPI-9016M inhibits cell proliferation in a dose-dependent manner in A549 and H1299 cells. The IC50 of BPI-9016M in several lung adenocarcinoma cell lines ( A549, H1299, H1650, H1975, HCC827, and PC-9 cells) as well as in primary lung adenocarcinoma cells are ranged from 5.3 μM to 27.1 μM.
In addition, BPI-9016M reduces expression of c-Met, p-c-Met, p-AKT and p-ERK in the H1299 and A549 cells.
Nextly, in lung adenocarcinoma patient-derived xenografts (PDX) NOD/SCID mice models. BPI-9016M dramatically suppresses tumor growth in PDX1, PDX2, and PDX3 xenografts after 16 or 12 days of treatment.
At the same time, BPI-9016M inhibits PDX4 xenografts without statistical significance.
The H-stores of PDX1, PDX2 and PDX3 tumors are 260, 210, 120, and the TGI values are 82.5%, 79.4%, 68.8% ,respectively.
However, PDX4 tumor exhibits H-store and TGI values of 20 and 32.5%, respectively.
Moreover, IHC of ki-67 also proves that BPI-9016M significantly inhibits tumor growth of lung adenocarcinoma, especially in tumors with overexpression.
In conclusion, BPI-9016M could inhibit proliferation, migration, and invasion in vitro, and suppresses tumor cell growth in vivo. It has the potential for lung cancer treatment.
Zhang P, et al. Theranostics. 2018 Nov 12;8(21):5890-5902.