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PF-06463922 CAS: 1454846-35-5

Category: Inhibitors
Product Name: PF-06463922
Cat No: I000027
CAS No: 1454846-35-5
Synonyms: (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 acetate
Molecular Formula: C21H19FN6O2
Molecular Weight: 406.4
SMILES: FC1=CC=C(C(N(C)CC2=NN(C)C(C#N)=C32)=O)C([C@@H](C)OC4=C(N)N=CC3=C4)=C1
InChI: InChI=1S/C21H19FN6O2/c1-11-15-7-13(22)4-5-14(15)21(29)27(2)10-16-19(17(8-23)28(3)26-16)12-6-18(30-11)20(24)25-9-12/h4-7,9,11H,10H2,1-3H3,(H2,24,25)/t11-/m1/s1
InChIKey: IIXWYSCJSQVBQM-LLVKDONJSA-N
Solubility: DMSO:≥ 28 mg/mL
Target: ALK
IC50: <0.02 nM/<0.07 nM/0.7 nM(Ki, ROS1/ALK (WT)/ALK (L1196M))
Storage: room temp
CAS 1454846-35-5,PF-06463922
  • Description

PF-06463922(cas 1454846-35-5) is a novel, orally available, CNS-penetrant, ATP-competitive inhibitor of ALK/ROS1 with Ki of <0.02 nM, <0.07 nM, and 0.7 nM for ROS1, ALK (WT), and ALK (L1196M), respectively.

in vitro: PF-06463922 demonstrates significant cell activity against ALK and a large set of ALK clinical mutations with IC50 ranging from 0.2 nM-77 nM . PF-06463922 exhibited subnanomolar cellular potency against oncogenic ROS1 fusions and inhibited the crizotinib-refractory ROS1(G2032R) mutation and the ROS1(G2026M) gatekeeper mutation. Compared with crizotinib and the second-generation ALK/ROS1 inhibitors ceritinib and alectinib, PF-06463922 showed significantly improved inhibitory activity against ROS1 kinase.
in vivo: PF-06463922 showed marked antitumor activity in tumor models expressing FIG-ROS1, CD74-ROS1, and the CD74-ROS1(G2032R) mutation. Furthermore, PF-06463922 demonstrated antitumor activity in a genetically engineered mouse model of FIG-ROS1 glioblastoma.

  • Spec

Appearance:White to off-white solid powder
Purity: > 98%

  • References


1:The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN. Guan J, Tucker ER, Wan H, Chand D, Danielson LS, Ruuth K, El Wakil A, Witek B, Jamin Y, Umapathy G, Robinson SP, Johnson TW, Smeal T, Martinsson T, Chesler L, Palmer RH, Hallberg B.Dis Model Mech. 2016 Sep 1;9(9):941-52. doi: 10.1242/dmm.024448. Epub 2016 Jul 7. PMID: 27483357 Free PMC Article
2:Conformational Studies and Atropisomerism Kinetics of the ALK Clinical Candidate Lorlatinib (PF-06463922) and Desmethyl Congeners. Elleraas J, Ewanicki J, Johnson TW, Sach NW, Collins MR, Richardson PF.Angew Chem Int Ed Engl. 2016 Mar 7;55(11):3590-5. doi: 10.1002/anie.201509240. Epub 2016 Feb 16. PMID: 26880581
3:The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma. Infarinato NR, Park JH, Krytska K, Ryles HT, Sano R, Szigety KM, Li Y, Zou HY, Lee NV, Smeal T, Lemmon MA, Mossé YP.Cancer Discov. 2016 Jan;6(1):96-107. doi: 10.1158/2159-8290.CD-15-1056. Epub 2015 Nov 10. PMID: 26554404 Free PMC Article
4:PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models. Zou HY, Friboulet L, Kodack DP, Engstrom LD, Li Q, West M, Tang RW, Wang H, Tsaparikos K, Wang J, Timofeevski S, Katayama R, Dinh DM, Lam H, Lam JL, Yamazaki S, Hu W, Patel B, Bezwada D, Frias RL, Lifshits E, Mahmood S, Gainor JF, Affolter T, Lappin PB, Gukasyan H, Lee N, Deng S, Jain RK, Johnson TW, Shaw AT, Fantin VR, Smeal T.Cancer Cell. 2015 Jul 13;28(1):70-81. doi: 10.1016/j.ccell.2015.05.010. Epub 2015 Jul 2. PMID: 26144315 Free PMC Article
5:NPM/ALK mutants resistant to ASP3026 display variable sensitivity to alternative ALK inhibitors but succumb to the novel compound PF-06463922. Mologni L, Ceccon M, Pirola A, Chiriano G, Piazza R, Scapozza L, Gambacorti-Passerini C.Oncotarget. 2015 Mar 20;6(8):5720-34. PMID: 25749034 Free PMC Article
6:PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. Zou HY, Li Q, Engstrom LD, West M, Appleman V, Wong KA, McTigue M, Deng YL, Liu W, Brooun A, Timofeevski S, McDonnell SR, Jiang P, Falk MD, Lappin PB, Affolter T, Nichols T, Hu W, Lam J, Johnson TW, Smeal T, Charest A, Fantin VR.Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3493-8. doi: 10.1073/pnas.1420785112. Epub 2015 Mar 2. PMID: 25733882 Free PMC Article
7: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. Johnson TW, Richardson PF, Bailey S, Brooun A, Burke BJ, Collins MR, Cui JJ, Deal JG, Deng YL, Dinh D, Engstrom LD, He M, Hoffman J, Hoffman RL, Huang Q, Kania RS, Kath JC, Lam H, Lam JL, Le PT, Lingardo L, Liu W, McTigue M, Palmer CL, Sach NW, Smeal T, Smith GL, Stewart AE, Timofeevski S, Zhu H, Zhu J, Zou HY, Edwards MP.J Med Chem. 2014 Jun 12;57(11):4720-44. doi: 10.1021/jm500261q. Epub 2014 Jun 3. PMID: 24819116


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