Neladalkib | CAS#2739866-40-9 | AlK inhibitor

MedKoo Cat#: 126540 | Name: Neladalkib

Description:

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

Neladalkib, also known as NVL-655, and NUV-655, is a selective, brain-penetrant ALK inhibitor with antitumor activity against the lorlatinib-resistant G1202R/L1196M compound mutation. NUV-655 (NVL-655) inhibited the kinase activity of ALK and ALK G1202R/L1196M with Kiapp < 5 nM in the presence of 1 mM ATP and with selectivity over TRKB. Across a panel of 335 wild-type kinases, NUV-655 (NVL-655) inhibited only 5 other kinases by >50% within 10-fold of its IC50 for ALK. NUV-655 (NVL-655) also selectively inhibited ALK in cells. It inhibited the growth of Ba/F3 cells driven by expression of EML4-ALK variant 1 (v1) with either wild-type kinase domain or drug-resistance mutations G1202R, G1202R/L1196M, or G1202R/G1269A at IC50 values < 10 nM and with selectivity over TRKB. In vivo, NUV-655 (NVL-655) induced regression at well-tolerated doses in a Ba/F3 EML4-ALKv1 G1202R/L1196M xenograft model. Furthermore, NUV-655 (NVL-655) demonstrated brain penetrance in rodent pharmacokinetic studies.

Chemical Structure

Neladalkib

CAS#2739866-40-9

Theoretical Analysis

MedKoo Cat#: 126540

Name: Neladalkib

CAS#: 2739866-40-9

Chemical Formula: C23H22ClFN6O

Exact Mass: 452.1528

Molecular Weight: 452.92

Elemental Analysis: C, 60.99; H, 4.90; Cl, 7.83; F, 4.19; N, 18.56; O, 3.53

Price and Availability

Size	Price	Availability
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,350.00	Ready to ship
500mg	USD 2,850.00	Ready to ship

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Related CAS #

2739866-40-9

Synonym

Nefextinib, NVL-655; NVL 655; NVL655; NUV-655; NUV 655; NUV655; ALK-IN-27

IUPAC/Chemical Name

(R)-1-chloro-3-ethyl-12-fluoro-10,16-dimethyl-3,10,16,18-tetrahydro-4,8-(metheno)benzo[l]dipyrazolo[3,4-g:4',3'-j][1]oxa[4]azacyclotetradecin-7-amine

InChi Key

FWZSCAQEBTVTOM-GFCCVEGCSA-N

InChi Code

InChI=1S/C23H22ClFN6O/c1-4-31-21-13-8-19(23(26)27-10-13)32-12(2)17-9-15(25)5-6-16(17)20-14(11-30(3)28-20)7-18(21)22(24)29-31/h5-6,8-12H,4,7H2,1-3H3,(H2,26,27)/t12-/m1/s1

SMILES Code

FC1=CC([C@](C)([H])OC2=C(N)N=CC3=C2)=C(C4=NN(C)C=C4CC5=C3N(N=C5Cl)CC)C=C1

Appearance

To be determined

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

To be determined

Shelf Life

>2 years if stored properly

Drug Formulation

To be determined

Stock Solution Storage

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

HS Tariff Code

2934.99.9001

More Info

ALK is a proto-oncogene that encodes the receptor tyrosine kinase ALK, which can be aberrantly activated by gene rearrangement or point mutation to drive tumor cell proliferation, survival, and metastasis. In advanced non-small cell lung cancer (NSCLC), ALK rearrangements are detected in about 4% of patients; at the time of diagnosis, 30% to 40% of these patients present with accompanying central nervous system (CNS) metastases. Brain-penetrant tyrosine kinase inhibitors (TKIs) alectinib, brigatinib, ceritinib, and lorlatinib are FDA-approved treatments for ALK-positive NSCLC; however, durability of response to these treatments has been limited in many cases by the emergence of mutations in ALK that confer resistance. A major resistance mutation to alectinib, brigatinib, and ceritinib is the ALK G1202R solvent front mutation. Although patients with tumors harboring the ALK G1202R mutation have responded to lorlatinib, many have subsequently relapsed by emergence of ALK compound mutations, such as G1202R/L1196M and G1202R/G1269A. Novel ALK inhibitor NUV-655 (NVL-655) was designed for broader coverage of ALK resistance mutations, activity in the CNS, and selectivity over structurally related tropomyosin receptor kinase B (TRKB). Avoiding TRKB inhibition is preferred, as CNS adverse events associated with TRKB inhibition have been reported for brain-penetrant TKIs

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#T24D07P18

QC Data

View QC data: current batch, Lot#T24D07P18

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Neladalkib is an investigational drug targeting the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase. It is specifically designed to inhibit ALK, including its resistant mutant forms, and is utilized in the treatment of ALK-positive cancers, such as non-small cell lung cancer (NSCLC). Neladalkib's development aims to address limitations of existing ALK inhibitors by targeting a broader range of ALK mutations and potentially offering enhanced efficacy and selectivity.

In vitro activity:

In vivo activity:

1. In vivo studies of NVL-655 demonstrate its effectiveness in targeting ALK-positive non-small cell lung cancer (NSCLC) with resistance mutations, including G1202R, G1202R/L1196M, and G1202R/G1269A. NVL-655 was well-tolerated and showed promising tumor regression in xenograft models, with effective brain penetration and minimal inhibition of the TRKB kinase, reducing potential CNS-related side effects. Its selectivity and activity against challenging ALK mutations highlight its potential as a valuable treatment option for patients with resistant ALK-positive NSCLC. Reference: Henry E. Pelish, Anupong Tangpeerachaikul, Nancy E. Kohl, James R. Porter, Matthew D. Shair, Joshua C. Horan; Abstract 1468: NUV-655 (NVL-655) is a selective, brain-penetrant ALK inhibitor with antitumor activity against the lorlatinib-resistant G1202R/L1196M compound mutation. Cancer Res 1 July 2021; 81 (13_Supplement): 1468.

	Solvent	mg/mL	mM
Solubility
	DMSO	100.0	220.79

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 452.92 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:

Henry E. Pelish, Anupong Tangpeerachaikul, Nancy E. Kohl, James R. Porter, Matthew D. Shair, Joshua C. Horan; Abstract 1468: NUV-655 (NVL-655) is a selective, brain-penetrant ALK inhibitor with antitumor activity against the lorlatinib-resistant G1202R/L1196M compound mutation. Cancer Res 1 July 2021; 81 (13_Supplement): 1468. https://doi.org/10.1158/1538-7445.AM2021-1468

In vitro protocol:

In vivo protocol:

1: Ou SI, Nagasaka M, Brazel D, Hou Y, Zhu VW. Will the clinical development of 4th-generation "double mutant active" ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC? Transl Oncol. 2021 Nov;14(11):101191. doi: 10.1016/j.tranon.2021.101191. Epub 2021 Aug 5. PMID: 34365220; PMCID: PMC8353359. 2: Desai A, Lovly CM. Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review. Transl Lung Cancer Res. 2023 Mar 31;12(3):615-628. doi: 10.21037/tlcr-22-708. Epub 2023 Mar 20. PMID: 37057106; PMCID: PMC10087990. 3: Lee ATM, Ou SI. Overcoming Central β-Sheet #6 (Cβ6) ALK Mutation (L1256F), TP53 Mutations and Short Forms of EML4-ALK v3/b and v5a/b Splice Variants are the Unmet Need That a Re-Imagined 5th- Generation (5G) ALK TKI Must Deliver. Lung Cancer (Auckl). 2024 Feb 27;15:19-27. doi: 10.2147/LCTT.S446878. PMID: 38433979; PMCID: PMC10908247.