Navitoclax

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Navitoclax
Names
Preferred IUPAC name
4-(4-{[2-(4-Chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-(trifluoromethanesulfonyl)benzene-1-sulfonyl)benzamide
Other names
ABT263; ABT-263
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
UNII
  • 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
    Key: JLYAXFNOILIKPP-KXQOOQHDSA-N
  • InChI=1/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
    Key: JLYAXFNOILIKPP-KXQOOQHDBT
  • CC1(CCC(=C(C1)CN2CCN(CC2)C3=CC=C(C=C3)C(=O)NS(=O)(=O)C4=CC(=C(C=C4)N[C@H](CCN5CCOCC5)CSC6=CC=CC=C6)S(=O)(=O)C(F)(F)F)C7=CC=C(C=C7)Cl)C
Properties
C47H55ClF3N5O6S3
Molar mass 974.61 g·mol−1
Pharmacology
L01XX78 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Navitoclax (previously ABT-263) is an experimental orally active anti-cancer drug, which is a Bcl-2 inhibitor similar in action to obatoclax.[1][2]

Mechanism of action

Navitoclax inhibits not only Bcl-2, but also Bcl-XL and Bcl-w proteins.[3] Because navitoclax inhibits Bcl-XL, it reduces platelet lifespan, causing thrombocytopenia, and this makes it dose-limiting.[citation needed]

Effects against senescent cells

In animal studies, navitoclax was found to be a senolytic agent, inducing apoptosis in senescent, but not non-senescent cells.[4] Oral administration of ABT263 to either sublethally irradiated or normally aged mice reduced senescent cells, including senescent bone marrow hematopoietic stem cells and senescent muscle stem cells. This depletion mitigated total-body irradiation-induced premature aging of the hematopoietic system and rejuvenated the aged hematopoietic stem cells and muscle stem cells in normally aged mice.[5]

On September 19, 2018, an article was published in Nature about using this drug to kill senescent glial cells in mice. The drug had a protective effect against memory loss in mice genetically engineered to simulate Alzheimer's Disease.[6]

Clinical trials

ABT-263 was studied in 2009.[7] In January 2017, Navitoclax was evaluated as a combination treatment against solid tumors together with trametinib in a clinical trial sponsored by the National Cancer Institute.[8] In this phase Ib/II study, patients with RAS-mutant tumors were enrolled to received trametinib plus navitoclax in dose-escalation part followed by multiple dose expansion cohorts.

In ESMO Congress 2023, the final results of 91 patients (including 38 patients from dose escalation part) were reported. At RP2D, 8/49 (16.3%) evaluable patients had a partial response (PR) with disease control rate (DCR) 59.2%. Though 35.2% objective response rate (0RR) and a disease control rate (DCR) of 85.7% was achieved among the 32 patients with GYN cancers, but the median duration of response (DOR) of 8.2 months was only moderately fine and no complete response was achieved.[9]

The product is currently under development by AbbVie. Navitoclax as mono-therapy[10][11] as well as in combination with chemotherapies (paclitaxel, docetaxel, gemcitabine, and irinotecan), olaparib,[12] erlotinib,[13] venetoclax,[14] and rituximab[15] in advanced hematological malignancies (in both pediatric and adult patients) and solid tumors including ovarian cancer, breast cancer, lung cancer.

In addition, a global multi-center, randomized, open-label, phase 3 study evaluating efficacy and safety of navitoclax in combination with ruxolitinib versus best available therapy in adult patients with relapsed/refractory myelofibrosis was initiated at 31 Aug, 2020 and is on recruiting (NCT04468984).

Antisclerotic

Not directly related to cancer, rather as a therapy for scleroderma, Navitoclax appeared to reduce existing fibrosis through inducing apoptosis of myofibroblasts. Further research is required to elucidate the exact mechanisms and confirm studies.

References

  1. ^ Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu YL, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM (March 2011). "Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors". Journal of Clinical Oncology. 29 (7): 909–16. doi:10.1200/JCO.2010.31.6208. PMC 4668282. PMID 21282543.
  2. ^ Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, et al. (March 2015). "Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy". Science Translational Medicine. 7 (279): 279ra40. doi:10.1126/scitranslmed.aaa4642. PMID 25787766. S2CID 206686917.
  3. ^ Chen, J.; Jin, S.; Abraham, V.; Huang, X.; Liu, B.; Mitten, M. J.; Nimmer, P.; Lin, X.; Smith, M.; Shen, Y.; Shoemaker, A. R.; Tahir, S. K.; Zhang, H.; Ackler, S. L.; Rosenberg, S. H.; Maecker, H.; Sampath, D.; Leverson, J. D.; Tse, C.; Elmore, S. W. (2011). "The Bcl-2/Bcl-XL/Bcl-w Inhibitor, Navitoclax, Enhances the Activity of Chemotherapeutic Agents In Vitro and In Vivo". Molecular Cancer Therapeutics. 10 (12). Mol Cancer Ther. 2011 Dec;10(12):2340-9. doi: 10.1158/1535-7163.MCT-11-0415. Epub 2011 Sep 13.: 2340–9. doi:10.1158/1535-7163.MCT-11-0415. PMID 21914853.
  4. ^ Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, et al. (June 2016). "Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors". Aging Cell. 15 (3): 428–35. doi:10.1111/acel.12445. PMC 4854923. PMID 26711051.
  5. ^ Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, Krager K, Ponnappan U, Hauer-Jensen M, Meng A, Zhou D (January 2016). "Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice". Nature Medicine. 22 (1): 78–83. doi:10.1038/nm.4010. PMC 4762215. PMID 26657143.
  6. ^ Bussian, Tyler J.; Aziz, Asef; Meyer, Charlton F.; Swenson, Barbara L.; van Deursen, Jan M.; Baker, Darren J. (October 2018). "Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline". Nature. 562 (7728): 578–582. Bibcode:2018Natur.562..578B. doi:10.1038/s41586-018-0543-y. ISSN 1476-4687. PMC 6206507. PMID 30232451.
  7. ^ Hauck P, Chao BH, Litz J, Krystal GW (April 2009). "Alterations in the Noxa/Mcl-1 axis determine of small cell to the BH3 mimetic ABT-737". Molecular Cancer Therapeutics. 8 (4): 883–92. doi:10.1158/1535-7163.MCT-08-1118. PMID 19372561. S2CID 19245418.
  8. ^ National Cancer Institute (sponsor), Corcoran R. "Trametinib and Navitoclax in Treating Patients With Advanced or Metastatic Solid Tumors". ClinicalTrials.gov. National Institutes of Health. Retrieved 24 June 2017. ClinicalTrials.gov Identifier: NCT02079740
  9. ^ Corcoran, Ryan. "664P - Final results of a phase I/II study of combined BCL-xL and MEK inhibition with navitoclax and trametinib in KRAS or NRAS mutant advanced solid tumors".
  10. ^ Roberts, Andrew (10 February 2012). "Substantial Susceptibility of to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease". Journal of Clinical Oncology. 30 (5): 488–496. doi:10.1200/jco.2011.34.7898. PMC 4979082.
  11. ^ Joly, Florence (2022). "A phase II study of Navitoclax (ABT-263) as single agent in women heavily pretreated for recurrent epithelial ovarian cancer: The MONAVI - GINECO study". Gynecologic Oncology. 165 (1): 30–39. doi:10.1016/j.ygyno.2022.01.021. PMID 35123771. S2CID 246499398.
  12. ^ Mackay, Helen (June 2023). "Exactis-03: A phase I trial of the combination of olaparib and navitoclax in women with high grade serous ovarian cancer and triple negative". Journal of Clinical Oncology. 41 (16_suppl): TPS5623. doi:10.1200/JCO.2023.41.16_suppl.TPS5623. S2CID 259080754.
  13. ^ Tolcher, Anthony (2015). "Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with in patients with advanced solid tumors. Cancer Chemother Pharmacol". Cancer Chemotherapy and Pharmacology. 76 (5): 1025–1032. doi:10.1007/s00280-015-2883-8. PMID 26420235. S2CID 23878408.
  14. ^ Pullarkat, Vinod (2021). "Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory and Lymphoblastic Lymphoma". Cancer Discovery. 11 (6): 1440–1453. doi:10.1158/2159-8290.CD-20-1465. PMC 9533326. PMID 33593877.
  15. ^ Kipps, Thomas (2015). "A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without , in previously untreated B-cell chronic lymphocytic leukemia". Leukemia & Lymphoma. 56 (10): 2826–2833. doi:10.3109/10428194.2015.1030638. PMC 4643417. PMID 25797560.
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