Lorlatinib (PF-06463922)

Catalog No.	APIM050226
Product Name	Lorlatinib (PF-06463922)

Description

APIM050226: Lorlatinib (PF-06463922)

A selective, orally active, brain-penetrant and ATP-competitive ROS1/ALK inhibitor.
CAS No.: 1454846-35-5
IUPAC/Chemical Name: (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile
Molecular Formula: C₂₁H₁₉FN₆O₂
Molecular Weight: 406.41
Purity: >99.5% Chemical Purity (HPLC at 215 and 254 nm), 100% Optical Purity (by Chiral HPLC)
Solubility: Soluble in DMSO
Storage: Store at 0^oC (short term), -20^oC (long term), Desiccated
Note: Please contact us for COA, Spectra, and SDS information.

Background Information:

Receptor tyrosine kinases (RTKs) are vital conduits of extracellular signals that direct cell growth and survival pathways. Unregulated RTK activation through chromosomal rearrangements, point mutations, and gene amplification has been shown to be responsible for the initiation and progression of many cancers. The orphan RTK c-ros oncogene1 (ROS1) normally is expressed transiently in various tissues during development with little to no expression in adult tissues. Elevated full-length c-ROS1 expression levels have been observed in 20–30% of patients with non-small cell lung cancer (NSCLC) by gene expression profiling and in 13% of patients with lung adenocarcinoma using immunohistochemistry (IHC). However, its function, both in normal physiology and disease, remains poorly defined mainly because of its still unidentified ligand. Chromosomal rearrangements resulting in oncogenic activation of ROS1 have been observed in a subset of patients with glioblastoma, NSCLC, cholangiocarcinoma, ovarian cancer, angiosarcoma, inflammatory myofibroblastic tumors, and Spitzoid melanoma. To date, interchromosomal translocations or intrachromosomal deletions have resulted in the production of 20 different N-terminal ROS1 fusion genes in a variety of cancers.

ROS1 is a distinct receptor with a kinase domain that is phylogenetically related to the anaplastic lymphoma kinase/lymphocyte-specific protein tyrosine kinase (ALK/LTK) and insulin receptor (INSR) RTK families, suggesting that tyrosine kinase inhibitors for these receptors could have cross-activity against ROS1. A recent phase I/II clinical trial designed to evaluate the safety and efficacy of the ALK/mesenchymal-epithelial transition factor (MET)/ROS1 inhibitor crizotinib in patients with ROS1 fusion-positive lung cancer demonstrated promising results. However, consistent with the clinical experience across a number of molecularly targeted kinase inhibitors, a subset of patients with ROS1 fusion kinase-positive cancer treated with crizotinib acquired mutations within the ROS1 kinase domain that confer drug resistance. Therefore, there is a clear need for the development of new agents to overcome crizotinib resistance.

ALK inhibitor PF-06463922 (lorlatinib) in neuroblastoma driven by expression of wild-type or mutant ALK, with a focus on whether PF-06463922 is more effective than crizotinib against those mutants known to confer crizotinib resistance. PF-06463922 is an orally available ATP-competitive selective inhibitor of ALK with excellent reported activity against both EML4-ALK as well as mutant EML4-ALK-resistant forms identified in patients treated with crizotinib. The oral availability and pharmacokinetic-pharmacodynamics of PF-06463922 have been previously investigated in a preclinical lung cancer setting where anti-tumor activity was robust and independent of administration route. Further, a preclinical evaluation of PF-06463922 displayed increased potency against acquired NSCLC ALK resistance mutations, with regression of EML4-ALK-driven brain metastases, and within the safety margins in a variety of preclinical studies. Currently, PF-06463922 is in phase 1/2 clinical trials for treatment of ALK-driven cancer (https://clinicaltrials.gov/; NCT01970865). PF-06463922 is a highly effective inhibitor in neuroblastoma cell lines, as well as in non-native (Ba/F3 and PC12) cell model systems that express neuroblastoma-specific ALK mutations. The observed in vitro cellular sensitivity to PF-06463922 aligns with its ability to inhibit kinase activity. In addition, PF-06463922 is effective in vivo in both subcutaneous and orthotopic xenograft models of neuroblastoma, as well as the Th-ALKF1174L/MYCN-driven transgenic neuroblastoma mouse model. Taken together, our data suggest that PF-06463922 may be a superior treatment for ALK-positive neuroblastoma, defined by the presence of kinase-activating point mutations. [3]

Target: ROS1 / ALK WT / ALK L1196M

Ki: < 0.02 nM (ROS1), < 0.07 nM (ALK WT), 0.7 nM (ALK L1196M)

In Vitro: Lorlatinib (PF-06463922) (CAS 1454846-35-5) demonstrates significant cell activity against ALK and a large set of ALK clinical mutations with IC50 ranging from 0.2 nM-77 nM. [1] Lorlatinib 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. Lorlatinib also shows potent growth inhibitory activity and induces apoptosis in the NSCLC cells harboring either non-mutant ALK or mutant ALK fusions.[2]

In Vivo: In rats, Lorlatinib (PF-06463922) (CAS 1454846-35-5) displays low plasma clearance, a moderate volume of distribution, a reasonable half-life, low propensity for p-glycoprotein 1-mediated efflux and a bioavailability of 100%. [1] In vivo, Lorlatinib shows cytoreductive antitumor efficacy in the NIH3T3 xenograft models expressing human CD74-ROS1 and Fig-ROS1 via inhibition in ROS1 phosphorylation and the downstream signaling molecules, as well as inhibition of the cell cycle protein Cyclin D1 in tumors. Lorlatinib also demonstrates marked antitumor activity in mice bearing tumor xenografts expressing EML4-ALK, EML4-ALK-L1196M, EML4-ALK-G1269A, EML4-ALK-G1202R or NPM-ALK. [2]

What is the solubility of Lorlatinib (CAS 1454846-35-5) in vitro?
DMSO: 28 mg/mL

What is the solubility of Lorlatinib (CAS 1454846-35-5) in vivo?
1. Solvent: DMSO, PEG300, Tween-80, and saline
Please add 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline in order; solubility ≥ 2.5mg/mL.
2. DMSO and 20% SBE-β-CD in salin
Please add 10% DMSO and 90% (20% SBE-β-CD in saline) in order; solubility 2.5 mg/mL.
3. DMSO and corn oil
Please add 0% DMSO and 90% corn oil in order, solubility ≥ 2.5 mg/mL.

Reference:
[1]. Johnson, T. W. et al. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations, J. Med. Chem., 2014, 57, 4720-4744
[2]. Zou, H. Y. et al. PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations, Proc. Natl. Acad. Sci. USA 2015, 112, 3493-8.
[3]. Guan, J. et al. The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN, Dis. Model Mech. 2016, 9, 941-952.
[4]. Collier, T. L. et al. Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib, Nat. Commun. 2017, 8, 15761. https://doi.org/10.1038/ncomms15761
[5]. Collier, T. L. et al. The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma, Cancer Discov. 2016, DOI: 10.1158/2159-8290.CD-15-1056

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CAS No.: 1454846-35-5

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