Definition
ChEBI: Lorlatinib is a cyclic ether that is 16,17-dihydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecin-15(10H)-one substituted by methyl groups at positions 2 and 10R, and by cyano, amino and fluoro groups at positions 3, 7 and 12 respectively. It is a small molecule inhibitor of ALK and ROS1 kinase developed by Pfizer for the treatment of ALK-positive non-small cell lung cancer. It has a role as an antineoplastic agent and an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor. It is a member of pyrazoles, a member of monofluorobenzenes, an aromatic ether, a nitrile, a member of benzamides, an azamacrocycle, an aminopyridine, a cyclic ether and an organic heterotetracyclic compound.
General Description
Class: receptor tyrosine kinase;
Treatment: NSCLC; Oral bioavailability = 81%; Elimination half-life = 24 h; Protein binding = 66%
Biological Activity
pf-06463922 is a potent and selective alk/ros1 inhibitor with ic50 values ranging from 0.19-0.53 nm for the kinase activity of ros1 fusion enzymes [1].the receptor tyrosine kinase c-ros oncogene1 (ros1) is a receptor with a kinase domain that is related to the anaplastic lymphoma kinase/lymphocyte-specific protein tyrosine kinase (alk/ltk) and insulin receptor (insr) rtk families [1].via cellular ros1 autophosphorylation in the recombinant enzyme assay, pf-06463922 showed a 30-fold improved potency against ros1, compared with crizotinib, ceritinib, alectinib and foretinib (xl-880). engineered nih 3t3 cells were expressing oncogenic human ros1 fusions. in these cells, pf-06463922 was more potent than foretinib and crizotinib by >10 folds, more potent than alectinib and ceritinib by >100 folds against cellular ros1 autophosphorylation [1].oncogenic gene fusions involving the 3' region of ros1 kinase had been found in various human cancers [2]. mice bearing cd74-ros1, cd74-ros1g2032r and fig-ros1(s) s.c. tumors (250 mm3) were used. treatments with pf-06463992 at various doses were applied consecutively for 7 or 9 d. at dosages of 0.2 to 1 mg/kg/d, pf-06463922 significantly inhibited the growth of both established figros1(s) and cd74-ros1 tumors compared with vehicle control. at 2-6 mg/kg/d, pf-06463922 significantly made tumor volumes regress (58–85%, p < 0.0001). in animals bearing nih 3t3-cd74-ros1g2032r tumors, treatment with pf-06463922 at 1.0, 3.0, and 10 mg/kg/d significantly inhibited tumor growth by 28%, 44% and 90%, respectively. at 30 mg/kg/d, pf-06463922 made tumor regress by 12%, compared with vehicle [1].
Enzyme inhibitor
This potent, dual ALK/ROS1 inhibitor (FW = 406.41 g/mol; CAS 1454846-
35-5), also named (10R) -7-amino-12-fluoro-10,15,16,17-tetrahydro-
2,10,16-trimethyl-15-oxo-2H-4,8-methenopyrazolo[4,3-
h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile, targets the proto-
oncogene tyrosine-protein kinase ROS1 (Ki < 0.02 nM) as well as wild-type
anaplastic lymphoma kinase ALKWT (Ki < 0.07 nM) and its Leu-to-Met
mutant ALKL1196M (K of = 0.7 nM). PF-06463922 significantly inhibits
i
cell proliferation and induces cell apoptosis in the HCC78 human NSCLC
cells harboring SLC34A2-ROS1 fusions and the BaF3-CD74-ROS1 cells
expressing human CD74-ROS1.
target
Primary targets: ALK/ROS1
References
[1]. zou hy, li q, engstrom ld, et al. pf-06463922 is a potent and selective next-generation ros1/alk inhibitor capable of blocking crizotinib-resistant ros1 mutations. proceedings of the national academy of sciences, 2015, 112(11): 3493-3498.
[2]. davies kd, le at, theodoro mf, et al. identifying and targeting ros1 gene fusions in non–small cell lung cancer. clinical cancer research, 2012, 18(17): 4570-4579.
