Lorlatinib acetate  (Synonyms: PF-06463922 acetate)

Lorlatinib (PF-06463922) acetate is a selective, orally active, brain-penetrant and ATP-competitive ROS1/ALK inhibitor with anticancer activity. Lorlatinib acetate has K_is of <0.025 nM, <0.07 nM, and 0.7 nM for ROS1, wild type ALK, and ALK^L1196M, respectively. Lorlatinib acetate targets to EML4-ALK, and inhibits ALK phosphorylation with IC₅₀s of 15-43 nM (ALK^L1196), 14-80 nM (ALK^G1269A), 38-50 nM (ALK^1151Tins), 77-113 nM (ALK^G1202R), respectively^[1][2][3].

Lorlatinib (PF-06463922) acetate 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 acetate 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 acetate also shows potent growth inhibitory activity and induces apoptosis in the NSCLC cells harboring either non-mutant ALK or mutant ALK fusions^[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

In rats, Lorlatinib (PF-06463922) 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].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

466.46

C₂₃H₂₃FN₆O₄

1924207-18-0

CN1C(C#N)=C2C(CN(C)C(C3=C([C@@H](C)OC4=C(N)N=CC2=C4)C=C(F)C=C3)=O)=N1.OC(C)=O

Room temperature in continental US; may vary elsewhere.

Please store the product under the recommended conditions in the Certificate of Analysis.

• [1]. Zou HY, et al. PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models. Cancer Cell. 2015 Jul 13;28(1):70-81.  [Content Brief]

  [2]. Johnson TW, 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 Jun 12;57(11):4720-44.  [Content Brief]

  [3]. Zou HY, et al. PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking PF-02341066-resistant ROS1 mutations. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3493-8  [Content Brief]