Lorlatinib | PF-06463922 | CAS#1454846-35-5 | ALK/ROS1 inhibitor

MedKoo Cat#: 406533 | Name: Lorlatinib (PF-06463922)

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Lorlatinib, also known as PF-06463922, is an orally available, ATP-competitive inhibitor of the receptor tyrosine kinases, anaplastic lymphoma kinase (ALK) and C-ros oncogene 1 (Ros1), with potential antineoplastic activity. Upon administration, ALK/ROS1 inhibitor PF-06463922 binds to and inhibits both ALK and ROS1 kinases. The kinase inhibition leads to disruption of ALK- and ROS1-mediated signaling and eventually inhibits tumor cell growth in ALK- and ROS1-overexpressing tumor cells. In addition, PF-06463922 is able to cross the blood brain barrier.

Chemical Structure

Lorlatinib (PF-06463922)

CAS#1454846-35-5 (free base)

Theoretical Analysis

MedKoo Cat#: 406533

Name: Lorlatinib (PF-06463922)

CAS#: 1454846-35-5 (free base)

Chemical Formula: C21H19FN6O2

Exact Mass: 406.1554

Molecular Weight: 406.41

Elemental Analysis: C, 62.06; H, 4.71; F, 4.67; N, 20.68; O, 7.87

Price and Availability

Size	Price	Availability
10mg	USD 90.00	Ready to ship
50mg	USD 250.00	Ready to ship
100mg	USD 450.00	Ready to ship
200mg	USD 750.00	Ready to ship
500mg	USD 1,450.00	Ready to Ship
1g	USD 2,450.00	Ready to ship
2g	USD 4,150.00	Ready to ship

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Related CAS #

1924207-18-0 (acetate) 2135926-03-1 (maleate) 1454846-35-5 (free base) 2306217-64-9 (hydrate)

Synonym

PF06463922; PF 06463922; PF-06463922; PF-6463922; PF6463922; PF 6463922; Lorlatinib;

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.

InChi Key

IIXWYSCJSQVBQM-LLVKDONJSA-N

InChi Code

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

SMILES Code

N#CC1=C(C(CN2C)=NN1C)C3=CN=C(N)C(O[C@H](C)C4=CC(F)=CC=C4C2=O)=C3

Appearance

White to off-white solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.09.01

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#T23D04P11

View CoA: current batch, Lot#T20D09P21

QC Data

View QC data: current batch, Lot#T20D09P21

View QC data: current batch, Lot#T23D04P11

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Lorlatinib is a ROS1/ALK inhibitor with Kis of <0.025 nM, <0.07 nM, and 0.7 nM for ROS1, wild type ALK, and ALKL1196M, respectively.

In vitro activity:

To compare PF-06463922 and crizotinib over a broader range of ALK-driven tumors, their abilities to inhibit growth of a range of cell-lines in vitro were assessed. As shown in Fig. 4 and Table S1, IC50 values measured for PF-06463922 in neuroblastoma cell-lines dependent on R1275Q-mutated ALK were 51-fold (NB-1643) and 19-fold (LAN-5) lower than those measured for crizotinib (Fig. 4A and B) – which themselves were ~310 nM. Importantly, IC50 values for PF-06463922 inhibition of cell-lines driven by the ALK-resistant F1174L ALK variant were also much lower – falling in the range of 12.7 nM to 26.6 nM, which is ~30-fold lower than measured for crizotinib (Fig. 4C–F and Table S1). A similar difference was also seen for Felix cells, driven by the F1245C variant (Fig. 4G). Whereas a small (~3-fold) difference in IC50 appeared to be sufficient to explain the relative crizotinib resistance of tumors and cell-lines driven by F1174L-mutated ALK in neuroblastoma compared with those driven by R1275Q (11), the overall higher potency of PF-06463922 appears to render such differences irrelevant – so that both tumor cell-lines (Fig. 4) and xenografts (Fig. 2) driven by the F1174L variant are sensitive to PF-06463922. The same appears to be true for the F1245C variant. Similar results were seen for NB-1 cells, driven by amplified wild-type ALK – with IC50 values of 256 nM and 5.2 nM for crizotinib and PF-06463922 respectively (Fig. 4H). Reference: Cancer Discov. 2016 Jan;6(1):96-107. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707106/

In vivo activity:

The in vivo efficacy of PF-06463922 was examined in patient-derived xenografts (PDXs) harboring F1174L or F1245C ALK mutations (COG-N-453x and Felix-PDX respectively), as well as cell line-derived xenografts utilizing SH-SY5Y cells (F1174L) or NB-1643 cells (R1275Q). Treatment with 10 mg/kg/day PF-06463922 (5 mg/kg BID) resulted in rapid (within 2–3 weeks) and sustained complete tumor regression for the duration of treatment in all xenografts (red curves in Fig. 2, and Table 1A). After PF-06463922 treatment was stopped, animals were further monitored for tumor progression by observation and palpation. Mice that had been treated with 10 mg/kg/day PF-06463922 remained in complete remission with no discernible tumor growth for a further 4.8 weeks (COG-N-453x), 7.1 weeks (Felix-PDX), 5 weeks (SH-SY5Y) and 4 weeks (NB-1643), as shown in Fig. S2A–D. Thus, xenografts harboring the ALK F1174L mutation exhibited unprecedented anti-tumor responses to single agent ALK inhibition therapy with PF-06463922, as did a PDX harboring the F1245C mutation. Reference: Cancer Discov. 2016 Jan;6(1):96-107. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707106/

	Solvent	mg/mL	mM
Solubility
	DMSO	38.0	93.50
	DMF	5.0	12.30
	Ethanol	15.5	38.14
	Ethanol:PBS (pH 7.2) (1:1)	0.5	1.23

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 406.41 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Infarinato NR, Park JH, Krytska K, Ryles HT, Sano R, Szigety KM, Li Y, Zou HY, Lee NV, Smeal T, Lemmon MA, Mossé YP. The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma. Cancer Discov. 2016 Jan;6(1):96-107. doi: 10.1158/2159-8290.CD-15-1056. Epub 2015 Nov 10. PMID: 26554404; PMCID: PMC4707106.

In vitro protocol:

In vivo protocol:

1: Liu G, Mazieres J, Stratmann J, Ou SI, Mok T, Grizzard M, Goto Y, Felip E, Solomon BJ, Bauer TM. A pragmatic guide for management of adverse events associated with lorlatinib. Lung Cancer. 2024 Mar 15;191:107535. doi: 10.1016/j.lungcan.2024.107535. Epub ahead of print. PMID: 38554546. 2: Fabbri L, Di Federico A, Astore M, Marchiori V, Rejtano A, Seminerio R, Gelsomino F, De Giglio A. From Development to Place in Therapy of Lorlatinib for the Treatment of ALK and ROS1 Rearranged Non-Small Cell Lung Cancer (NSCLC). Diagnostics (Basel). 2023 Dec 25;14(1):48. doi: 10.3390/diagnostics14010048. PMID: 38201357; PMCID: PMC10804309. 3: Lingling X, Maoxi C, Wei Y, Jieting Z, Yuanyuan Y, Ning X. Transformation of NSCLC to SCLC harboring EML4-ALK fusion with V1180L mutation after alectinib resistance and response to lorlatinib: A case report and literature review. Lung Cancer. 2023 Dec;186:107415. doi: 10.1016/j.lungcan.2023.107415. Epub 2023 Oct 28. PMID: 37907052. 4: Liao D, Zhang J, Yan T, Chen S, Li W, Shangguan D, She Z. Recent Advances in the Management of Adverse Events Associated with Lorlatinib. Onco Targets Ther. 2023 Sep 5;16:731-738. doi: 10.2147/OTT.S426989. PMID: 37694103; PMCID: PMC10492578. 5: Kilickap S, Ak S, Dursun OU, Sendur MA, Karadurmus N, Demirci U. Safety of lorlatinib in ALK-positive non-small-cell lung cancer and management of central nervous system adverse events. Future Oncol. 2023 Sep;19(29):2003-2012. doi: 10.2217/fon-2023-0014. Epub 2023 Jul 14. PMID: 37449387. 6: Solomon BJ, Bauer TM, K Mok TS, Liu G, Mazieres J, Marinis F, Goto Y, Kim DW, Wu YL, Jassem J, López FL, Soo RA, Shaw AT, Polli A, Messina R, Iadeluca L, Toffalorio F, Felip E. Plain language summary of the updated results from the CROWN study comparing lorlatinib with crizotinib in people with advanced non- small-cell lung cancer. Future Oncol. 2023 May;19(14):961-973. doi: 10.2217/fon-2022-1289. Epub 2023 Jun 12. PMID: 37306090. 7: Ou SI, Lee ATM, Nagasaka M. From preclinical efficacy to 2022 (36.7 months median follow -up) updated CROWN trial, lorlatinib is the preferred 1st-line treatment of advanced ALK+ NSCLC. Crit Rev Oncol Hematol. 2023 Jul;187:104019. doi: 10.1016/j.critrevonc.2023.104019. Epub 2023 May 13. PMID: 37187318. 8: Riudavets M, Planchard D. An update on lorlatinib: a novel first line treatment for ALK-positive advanced lung cancer. Expert Opin Pharmacother. 2023 Feb;24(3):291-299. doi: 10.1080/14656566.2022.2161880. Epub 2023 Jan 1. PMID: 36542835. 9: Baba K, Goto Y. Lorlatinib as a treatment for ALK-positive lung cancer. Future Oncol. 2022 Aug;18(24):2745-2766. doi: 10.2217/fon-2022-0184. Epub 2022 Jul 5. PMID: 35787143. 10: Lorlatinib (Lorbrena): CADTH Reimbursement Recommendation: Indication: As monotherapy for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced (not amenable to curative therapy) or metastatic non–small cell lung cancer (NSCLC) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2022 Apr. PMID: 38232201. 11: Fallet V, Rouby P, Ahle G, Arrondeau J, Naltet C, Duflot-Boukobza A, De Crozals F, Lena H, Cortot A. Troubles du système nerveux central sous lorlatinib : comment les détecter et les gérer en pratique ? [Central nervous system disorders on lorlatinib: How to detect and manage in practice?]. Bull Cancer. 2022 Apr;109(4):477-490. French. doi: 10.1016/j.bulcan.2022.01.011. Epub 2022 Mar 4. PMID: 35256158. 12: Yun KM, Bazhenova LA. Update on Lorlatinib: Role in Reducing the Risk of Disease Progression in ALK-Positive NSCLC. Cancer Manag Res. 2022 Feb 26;14:843-850. doi: 10.2147/CMAR.S283199. PMID: 35250311; PMCID: PMC8890401. 13: Ando K, Manabe R, Kishino Y, Kusumoto S, Yamaoka T, Tanaka A, Ohmori T, Sagara H. Comparative Efficacy and Safety of Lorlatinib and Alectinib for ALK- Rearrangement Positive Advanced Non-Small Cell Lung Cancer in Asian and Non- Asian Patients: A Systematic Review and Network Meta-Analysis. Cancers (Basel). 2021 Jul 23;13(15):3704. doi: 10.3390/cancers13153704. PMID: 34359604; PMCID: PMC8345181. 14: McGee K, Stone NJ, Wadhwani S, Kanwar YS, Villaflor V, Akhter N. A possible mechanism of hyperlipidemia in a patient with metastatic non-small cell lung cancer on lorlatinib therapy. J Oncol Pharm Pract. 2021 Dec;27(8):2010-2013. doi: 10.1177/10781552211004698. Epub 2021 Mar 31. PMID: 33789526. 15: Lorlatinib for non-small cell lung cancer. Aust Prescr. 2020 Dec;43(6):216-217. doi: 10.18773/austprescr.2020.065. Epub 2020 Oct 22. PMID: 33363309; PMCID: PMC7738687. 16: Naito T, Shiraishi H, Fujiwara Y. Brigatinib and lorlatinib: their effect on ALK inhibitors in NSCLC focusing on resistant mutations and central nervous system metastases. Jpn J Clin Oncol. 2021 Jan 1;51(1):37-44. doi: 10.1093/jjco/hyaa192. PMID: 33147606. 17: El Darsa H, Abdel-Rahman O, Sangha R. Pharmacological and clinical properties of lorlatinib in the treatment of ALK-rearranged advanced non- small cell lung cancer. Expert Opin Pharmacother. 2020 Sep;21(13):1547-1554. doi: 10.1080/14656566.2020.1774552. Epub 2020 Jun 8. PMID: 32511029. 18: Nagasaka M, Ge Y, Sukari A, Kukreja G, Ou SI. A user's guide to lorlatinib. Crit Rev Oncol Hematol. 2020 Jul;151:102969. doi: 10.1016/j.critrevonc.2020.102969. Epub 2020 May 11. PMID: 32416346. 19: Choo JR, Soo RA. Lorlatinib for the treatment of ALK-positive metastatic non-small cell lung cancer. Expert Rev Anticancer Ther. 2020 Apr;20(4):233-240. doi: 10.1080/14737140.2020.1744438. Epub 2020 Mar 25. PMID: 32186215. 20: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–. Lorlatinib. 2019 Apr 15. PMID: 31643879.