Navitoclax
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MedKoo CAT#: 201970

CAS#: 923564-51-6

Description: Navitoclax, also known as ABT-263, is an orally bioavailable, synthetic small-molecule antagonist of a subset of the B-cell leukemia 2 (Bcl-2) family of proteins with potential antineoplastic activity. ABT-263 selectively binds to apoptosis suppressor proteins Bcl-2, Bcl-XL, and Bcl-w and prevents their binding to the apoptotic effectors Bax and Bak proteins, which may trigger apoptosis in tumor cells overexpressing Bcl-2, Bcl-XL, and Bcl-w.


Chemical Structure

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Navitoclax
CAS# 923564-51-6

Theoretical Analysis

MedKoo Cat#: 201970
Name: Navitoclax
CAS#: 923564-51-6
Chemical Formula: C47H55ClF3N5O6S3
Exact Mass: 973.29551
Molecular Weight: 974.61
Elemental Analysis: C, 57.92; H, 5.69; Cl, 3.64; F, 5.85; N, 7.19; O, 9.85; S, 9.87

Price and Availability

Size Price Availability Quantity
10.0mg USD 80.0 Ready to ship
50.0mg USD 110.0 Ready to ship
100.0mg USD 190.0 Ready to ship
200.0mg USD 350.0 Ready to ship
500.0mg USD 750.0 Ready to ship
1.0g USD 1350.0 Ready to ship
2.0g USD 2430.0 Ready to ship
5.0g USD 5450.0 Ready to ship
10.0g USD 9750.0 Ready to ship
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Synonym: ABT 263; ABT-263; ABT263; Navitoclax

IUPAC/Chemical Name: (R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide

InChi Key: JLYAXFNOILIKPP-KXQOOQHDSA-N

InChi Code: InChI=1S/C47H55ClF3N5O6S3/c1-46(2)20-18-42(34-8-12-37(48)13-9-34)36(31-46)32-55-22-24-56(25-23-55)39-14-10-35(11-15-39)45(57)53-65(60,61)41-16-17-43(44(30-41)64(58,59)47(49,50)51)52-38(19-21-54-26-28-62-29-27-54)33-63-40-6-4-3-5-7-40/h3-17,30,38,52H,18-29,31-33H2,1-2H3,(H,53,57)/t38-/m1/s1

SMILES Code: O=C(NS(=O)(C1=CC=C(N[C@H](CCN2CCOCC2)CSC3=CC=CC=C3)C(S(=O)(C(F)(F)F)=O)=C1)=O)C4=CC=C(N5CCN(CC6=C(C7=CC=C(Cl)C=C7)CCC(C)(C)C6)CC5)C=C4

Appearance: 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: 2934.99.9001

Biological target: Bcl-xL, Bcl-2 and Bcl-w inhibitor with Ki of ≤ 0.5 nM, ≤1 nM and ≤1 nM in cell-free assays.
In vitro activity: The MCC cell lines WaGa, MKL-1, MKL-2 and MCC13 as well as the B-ALL cell line REH were treated with different concentrations (range 1 nM to 1 µM) of the specific BCL-2 inhibitor Navitoclax (Figure 1I). With increasing concentrations, the cell viability decreased. For all cell lines except for BCL-2, negative MCC13 dose–response curves and IC50 values could be generated. MKL-1, WaGa and REH demonstrated similar high sensitivity towards Navitoclax treatment (IC50 around 100 nM). Surprisingly, MKL-2 was less sensitive (IC50 = 323.3 nM), although this cell line showed a high BCL-2 expression. Subsequently, BCL-2 inhibition was assessed to see if it promotes apoptosis in MCC cells, as assessed by the detection of cleaved PARP protein by apoptosis-activated caspases. Indeed, all cell lines except MCC13 (Figure 1L and andM)M) showed different levels of increase of cleaved PARP with incremental Navitoclax concentrations. Reference: Ther Adv Med Oncol. 2020; 12: 1758835920975621. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739210/
In vivo activity: Treatment with navitoclax plus ABT-414 caused a significant reduction in tumor growth in five of seven PDXs and significant tumor regression in the highest EGFR-expressing PDX. Navitoclax plus ABBV-321, an EGFR-targeted ADC that displays more effective wild-type EGFR-targeting, elicited more significant tumor growth inhibition and regressions in the two highest EGFR-expressing models evaluated. The level of mitochondrial apoptotic signaling induced by single or combined drug treatments, as measured by DBP, correlated with the treatment responses observed in vivo. Lastly, the majority of triple-negative patient tumors were found to express EGFR and co-express BCL-XL and/or BCL-2. Reference: Breast Cancer Res. 2020; 22: 132. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708921/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 25.0 25.7

Preparing Stock Solutions

The following data is based on the product molecular weight 974.61 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.

Recalculate based on batch purity %
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. Chteinberg E, Wetzels S, Gerritsen W, Temmerman L, van den Oord J, Biessen E, Kurz AK, Winnepenninckx V, Zenke M, Speel EJ, Zur Hausen A. Navitoclax combined with Alpelisib effectively inhibits Merkel cell carcinoma cell growth in vitro. Ther Adv Med Oncol. 2020 Dec 14;12:1758835920975621. doi: 10.1177/1758835920975621. PMID: 33403016; PMCID: PMC7739210. 2. Zoeller JJ, Vagodny A, Daniels VW, Taneja K, Tan BY, DeRose YS, Fujita M, Welm AL, Letai A, Leverson JD, Blot V, Bronson RT, Dillon DA, Brugge JS. Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer. Breast Cancer Res. 2020 Nov 30;22(1):132. doi: 10.1186/s13058-020-01374-8. PMID: 33256808; PMCID: PMC7708921. 2. Zoeller JJ, Vagodny A, Daniels VW, Taneja K, Tan BY, DeRose YS, Fujita M, Welm AL, Letai A, Leverson JD, Blot V, Bronson RT, Dillon DA, Brugge JS. Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer. Breast Cancer Res. 2020 Nov 30;22(1):132. doi: 10.1186/s13058-020-01374-8. PMID: 33256808; PMCID: PMC7708921.
In vitro protocol: 1. Chteinberg E, Wetzels S, Gerritsen W, Temmerman L, van den Oord J, Biessen E, Kurz AK, Winnepenninckx V, Zenke M, Speel EJ, Zur Hausen A. Navitoclax combined with Alpelisib effectively inhibits Merkel cell carcinoma cell growth in vitro. Ther Adv Med Oncol. 2020 Dec 14;12:1758835920975621. doi: 10.1177/1758835920975621. PMID: 33403016; PMCID: PMC7739210.
In vivo protocol: 1. Zoeller JJ, Vagodny A, Daniels VW, Taneja K, Tan BY, DeRose YS, Fujita M, Welm AL, Letai A, Leverson JD, Blot V, Bronson RT, Dillon DA, Brugge JS. Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer. Breast Cancer Res. 2020 Nov 30;22(1):132. doi: 10.1186/s13058-020-01374-8. PMID: 33256808; PMCID: PMC7708921.

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.1 Jochems F, Thijssen B, De Conti G, Jansen R, Pogacar Z, Groot K, Wang L, Schepers A, Wang C, Jin H, Beijersbergen RL, Leite de Oliveira R, Wessels LFA, Bernards R. The Cancer SENESCopedia: A delineation of cancer cell senescence. Cell Rep. 2021 Jul 27;36(4):109441. doi: 10.1016/j.celrep.2021.109441. PMID: 34320349.

1: Kaefer A, Yang J, Noertersheuser P, Mensing S, Humerickhouse R, Awni W, Xiong H. Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia. Cancer Chemother Pharmacol. 2014 Sep;74(3):593-602. doi: 10.1007/s00280-014-2530-9. Epub 2014 Jul 23. PubMed PMID: 25053389.

2: Yang J, Pradhan RS, Rosen LS, Graham AM, Holen KD, Xiong H. Effect of rifampin on the pharmacokinetics, safety and tolerability of navitoclax (ABT-263), a dual inhibitor of Bcl-2 and Bcl-X(L) , in patients with cancer. J Clin Pharm Ther. 2014 Jul 22. doi: 10.1111/jcpt.12193. [Epub ahead of print] PubMed PMID: 25047139.

3: Wei X, Zhou P, Lin X, Lin Y, Wu S, Diao P, Xie H, Xie K, Tang P. MLN2238 synergizes BH3 mimetic ABT-263 in castration-resistant prostate cancer cells by induction of NOXA. Tumour Biol. 2014 Jul 17. [Epub ahead of print] PubMed PMID: 25027405.

4: Suryani S, Carol H, Chonghaile TN, Frismantas V, Sarmah C, High L, Bornhauser B, Cowley MJ, Szymanska B, Evans K, Boehm I, Tonna E, Jones L, Manesh DM, Kurmasheva RT, Billups C, Kaplan W, Letai A, Bourquin JP, Houghton PJ, Smith MA, Lock RB. Cell and Molecular Determinants of In Vivo Efficacy of the BH3 Mimetic ABT-263 against Pediatric Acute Lymphoblastic Leukemia Xenografts. Clin Cancer Res. 2014 Sep 1;20(17):4520-31. doi: 10.1158/1078-0432.CCR-14-0259. Epub 2014 Jul 10. PubMed PMID: 25013123; PubMed Central PMCID: PMC4154988.

5: Polier G, Giaisi M, Köhler R, Müller WW, Lutz C, Buss EC, Krammer PH, Li-Weber M. Targeting CDK9 by wogonin and related natural flavones potentiates the anti-cancer efficacy of the Bcl-2 family inhibitor ABT-263. Int J Cancer. 2014 Jun 4. doi: 10.1002/ijc.29009. [Epub ahead of print] PubMed PMID: 24895203.

6: Vlahovic G, Karantza V, Wang D, Cosgrove D, Rudersdorf N, Yang J, Xiong H, Busman T, Mabry M. A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors. Invest New Drugs. 2014 Oct;32(5):976-84. doi: 10.1007/s10637-014-0116-3. Epub 2014 Jun 5. PubMed PMID: 24894650.

7: Wang X, Gu Z, Li G, Zhang S, Cao Z, Yang Z, Liu G. Norcantharidin enhances ABT-263-mediated anticancer activity in neuroblastoma cells by upregulation of Noxa. Oncol Rep. 2014 Aug;32(2):716-22. doi: 10.3892/or.2014.3228. Epub 2014 May 30. PubMed PMID: 24891300.

8: Wang B, Ni Z, Dai X, Qin L, Li X, Xu L, Lian J, He F. The Bcl-2/xL inhibitor ABT-263 increases the stability of Mcl-1 mRNA and protein in hepatocellular carcinoma cells. Mol Cancer. 2014 Apr 30;13:98. doi: 10.1186/1476-4598-13-98. PubMed PMID: 24779770; PubMed Central PMCID: PMC4021276.

9: Li J, Chen Y, Wan J, Liu X, Yu C, Li W. ABT-263 enhances sorafenib-induced apoptosis associated with Akt activity and the expression of Bax and p21((CIP1/WAF1)) in human cancer cells. Br J Pharmacol. 2014 Jul;171(13):3182-95. doi: 10.1111/bph.12659. PubMed PMID: 24571452; PubMed Central PMCID: PMC4080973.

10: Choo EF, Boggs J, Zhu C, Lubach JW, Catron ND, Jenkins G, Souers AJ, Voorman R. The role of lymphatic transport on the systemic bioavailability of the Bcl-2 protein family inhibitors navitoclax (ABT-263) and ABT-199. Drug Metab Dispos. 2014 Feb;42(2):207-12. doi: 10.1124/dmd.113.055053. Epub 2013 Nov 8. PubMed PMID: 24212376.



Additional Information

Bcl-2, Bcl-XL, and Bcl-w are frequently overexpressed in a wide variety of cancers, including those of the lymphatic system, breast, lung, prostate, and colon, and have been linked to tumor drug resistance.