Lorlatinib (PF-06463922) is a new drug under development for the sub-group of advanced non-small cell lung cancerwho are ALK or ROS1 positive and have already undergone gene treatment with drugs thatspecifically targetthis type of cancer.Lorlatinib is currently being evaluated in phase II clinical trials as an oral dose at 100 mg daily. If marketed it will becomean additional targeted treatment for this sub-group of ALKor ROS1 positive patients.
Lorlatinib acts by inhibiting the ALK and ROS1 receptor tyrosine kinases, with potent activity against a broad spectrum of ALK resistant mutations. By inhibiting ALK phosphorylation and ROS1 activity, lorlatinib inhibits the downstream signalling, thereby inducing the apoptosis process, which results in the inhibition of tumour cells proliferation.
Due to tumor complexity and development of resistance to treatment, disease progression is a challenge in patients with ALK-positive metastatic non-small cell lung cancer (NSCLC). A common site for progression in metastatic NSCLC is the brain.
Lorlatinib was specifically designed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier.
Lorlatinib is a kinase inhibitor with in vitro activity against ALK and number of other tyrosine kinase receptor related targets including ROS1, TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK Label. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors Label. Moreover, lorlatinib possesses the capability to cross the blood-brain barrier, allowing it to reach and treat progressive or worsening brain metastases as well. The overall antitumor activity of lorlatinib in in-vivo models appears to be dose-dependent and correlated with the inhibition of ALK phosphorylation Label.
Although many ALK-positive metastatic NSCLC patients respond to initial tyrosine kinase therapies, such patients also often experience tumor progression. Various clinical trials performed with lorlatinib, however, have demonstrated its utility to effect tumor regression in ALK-positive metastatic NSCLC patients who experience tumor progression despite current use or having already used various first and second-generation tyrosine kinase inhibitors like crizotinib, alectinib, or ceritinib.
Lorlatinib is a selective tyrosine kinase receptor inhibitor used in the therapy of selected cases of advanced non-small cell lung cancer.Lorlatinib has been used in trials studying the basic science and treatment of Non-small Cell Lung Cancer and anaplastic lymphoma kinase (ALK)-positive Non-Small Cell Lung Cancer (NSCLC) and ROS1-positive NSCLC. Despite initial responses from the use of various ALK inhibitors, however, it is virtually almost guaranteed that all patients with the condition in question will develop tumour progression or resistance to the current therapy in use.
A third-generation ALK- and ROS1-inhibitor, lorlatinib, has demonstrated activity following progression on one or more ALK inhibitors.Lorlatinib is approved for ALK-positive NSCLC. Similar to other agents in this category, lorlatinib is associated with hepatotoxicity and interstitial lung disease/pneumonitis. CNS toxicities, hyperlipidemia, and atrioventricular block have also been reported.
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that promotes cell proliferation and blocks apoptosis. PF-06463922 is an ATP-competitive, selective inhibitor of ALK (Ki = < 0.07 nM) and c-Ros oncogene 1 (ROS1, Ki = 0.7 nM). It has strong activity against all known ALK and ROS1 mutants identified in patients, including the EML4-L1196M mutant of ALK (Ki = < 0.02 nM). PF-06463922 is orally available, displaying inhibition of ALK phosphorylation and antitumor efficacy in a xenograft model expressing EML4-L1196M ALK. It demonstrates efficient blood-brain barrier penetration, produces brain tumor regression in mice harboring EML4-ALK tumors, and increases overall survival.[Cayman Chemical]
PF- 06463922 is a potent and selective ROS1/ALK inhibitor capable to block crizotinib-resistant ROS1 mutations. Used in the treatment of human cancers.
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.
Class: receptor tyrosine kinase;
Treatment: NSCLC; Oral bioavailability = 81%; Elimination half-life = 24 h; Protein binding = 66%
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].
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 protooncogene 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 (Ki of = 0.7 nM). PF-06463922 significantly inhibits 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
Primary targets: ALK/ROS1
[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.
