ABT-737: Difference between revisions

Add links
From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
m →‎top: Journal cites:, added 1 PMC
No edit summary
Line 29: Line 29:
}}
}}
}}
}}
'''ABT-737''' is a small [[molecule]] that specifically induces [[apoptosis]] in [[senescent cells]].<ref>{{cite journal | first1=Tilman | last1=Oltersdorf | first2=Steven W. | last2=Elmore | first3=Alexander R. | last3=Shoemaker | first4=Robert C. | last4=Armstrong | first5=David J. | last5=Augeri | first6=Barbara A. | last6=Belli | first7=Milan | last7=Bruncko | first8=Thomas L. | last8=Deckwerth | first9=Jurgen | last9=Dinges | first10=Philip J. | last10=Hajduk | first11=Mary K. | last11=Joseph | first12=Shinichi | last12=Kitada | first13=Stanley J. | last13=Korsmeyer | first14=Aaron R. | last14=Kunzer | first15=Anthony | last15=Letai | first16=Chi | last16=Li | first17=Michael J. | last17=Mitten | first18=David G. | last18=Nettesheim | first19=ShiChung | last19=Ng | first20=Paul M. |last20=Nimmer | first21=Jacqueline M. |last21=O'Connor | first22=Anatol |last22=Oleksijew | first23=Andrew M. |last23=Petros | first24=John C. | last24=Reed | first25=Wang | last25=Shen | first26=Stephen K. | last26=Tahir | first27=Craig B. |last27=Thompson | first28=Kevin J. | last28=Tomaselli |first29=Baole |last29=Wang |first30=Michael D. |last30=Wendt | first31=Haichao |last31=Zhang |first32=Stephen W. |last32=Fesik |first33=Saul H. |last33=Rosenberg | title = An inhibitor of Bcl-2 family proteins induces regression of solid tumours. | journal = [[Nature (journal)|Nature]] | year=2005 | volume=435 | issue=7042 | pages=677-81 | doi=10.1038/nature03579 | pmid=15902208| bibcode=2005Natur.435..677O }}</ref><ref>{{cite journal | first1=Reut |last1=Yosef | first2=Noam | last2=Pilpel | first3=Ronit |last3=Tokarsky-Amiel | first4=Anat |last4=Biran |first5=Yossi |last5=Ovadya | first6=Snir |last6=Cohen |first7=Ezra |last7=Vadai | first8=Liat |last8=Dassa |first9=Elisheva |last9=Shahar | first10=Reba |last10=Condiotti |first11=Ittai |last11=Ben-Porath | first12=Valery |last12=Krizhanovsky | title=Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL | journal = [[Nature Communications]] | year=2016 | volume=7 | page=11190 | pmid=27048913 | doi=10.1038/ncomms11190 |url=http://www.nature.com/ncomms/2016/160406/ncomms11190/full/ncomms11190.html|bibcode=2016NatCo...711190Y | pmc=4823827}}</ref>
'''ABT-737''' is a [[small molecule]] drug that inhibits [[Bcl-2]] and [[Bcl-xL]], two members of the [[Bcl-2 family]] of [[Conserved sequence|evolutionarily-conserved]] proteins that share '''B'''cl-2 [[Sequence homology|'''H'''omology]] (BH) [[protein domain|domain]]s. First developed as a potential [[cancer chemotherapy]],<ref name="CroceReed2016">{{cite journal |last1=Croce |first1=Carlo M |last2=Reed |first2=John C |title=Finally, An Apoptosis-Targeting Therapeutic for Cancer |journal=Cancer Research |date=October 2016 |volume=76 |issue=20 |pages=5914-5920 |doi=10.1158/0008-5472.CAN-16-1248 |pmid=27694602 |url=http://cancerres.aacrjournals.org/content/76/20/5914 |accessdate=30 September 2018}}</ref> it was subsequently identified as a [[senolytic]] (a drug that selectively induces [[cell death]] in [[senescent cells]]).<ref name=Yosef2016>{{cite journal | first1=Reut |last1=Yosef | first2=Noam | last2=Pilpel | first3=Ronit |last3=Tokarsky-Amiel | first4=Anat |last4=Biran |first5=Yossi |last5=Ovadya | first6=Snir |last6=Cohen |first7=Ezra |last7=Vadai | first8=Liat |last8=Dassa |first9=Elisheva |last9=Shahar | first10=Reba |last10=Condiotti |first11=Ittai |last11=Ben-Porath | first12=Valery |last12=Krizhanovsky | title=Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL | journal = [[Nature Communications]] | year=2016 | volume=7 | page=11190 | pmid=27048913 | doi=10.1038/ncomms11190 |url=http://www.nature.com/ncomms/2016/160406/ncomms11190/full/ncomms11190.html|bibcode=2016NatCo...711190Y | pmc=4823827}}</ref>


The Bcl-2 family is most notable for their regulation of [[apoptosis]], a form of programmed cell death, at the [[mitochondrion]]; Bcl-2 and Bcl-xL are anti-apoptotic proteins. Because many cancers have mutations in these genes that allow them to survive, scientists began working to develop drugs that would inhibit this pathway in the 1990s.<ref name="CroceReed2016"/> ABT-737 was one of the earliest of a series of drugs developed by [[Abbott Laboratories]] (now [[Abbvie]]) to target this pathway, based on their resolution of the 3D structure of Bcl-xL and studies using high-field solution [[nuclear magnetic resonance]] (NMR) that revealed how the BH domains of these proteins interacted with their targets.<ref name="CroceReed2016"/>
⚫
==References==
⚫
{{reflist}}


ABT-737 was superior to previous BCL-2 inhibitors given its higher affinity for Bcl-2, Bcl-xL and [[Bcl-w]]. ''In vitro'' studies showed that primary cells from patients with B-cell malignancies are sensitive to ABT-737.<ref>Vogler, Meike, et al. "Bcl-2 inhibitors: small molecules with a big impact on cancer therapy." Cell Death & Differentiation 16.3 (2008): 360–367.</ref> In animal models, it improved survival, caused tumor regression, and cured a high percentage of mice.<ref name=Tilman2005>{{cite journal | first1=Tilman | last1=Oltersdorf | first2=Steven W. | last2=Elmore | first3=Alexander R. | last3=Shoemaker | first4=Robert C. | last4=Armstrong | first5=David J. | last5=Augeri | first6=Barbara A. | last6=Belli | first7=Milan | last7=Bruncko | first8=Thomas L. | last8=Deckwerth | first9=Jurgen | last9=Dinges | first10=Philip J. | last10=Hajduk | first11=Mary K. | last11=Joseph | first12=Shinichi | last12=Kitada | first13=Stanley J. | last13=Korsmeyer | first14=Aaron R. | last14=Kunzer | first15=Anthony | last15=Letai | first16=Chi | last16=Li | first17=Michael J. | last17=Mitten | first18=David G. | last18=Nettesheim | first19=ShiChung | last19=Ng | first20=Paul M. |last20=Nimmer | first21=Jacqueline M. |last21=O'Connor | first22=Anatol |last22=Oleksijew | first23=Andrew M. |last23=Petros | first24=John C. | last24=Reed | first25=Wang | last25=Shen | first26=Stephen K. | last26=Tahir | first27=Craig B. |last27=Thompson | first28=Kevin J. | last28=Tomaselli |first29=Baole |last29=Wang |first30=Michael D. |last30=Wendt | first31=Haichao |last31=Zhang |first32=Stephen W. |last32=Fesik |first33=Saul H. |last33=Rosenberg | title = An inhibitor of Bcl-2 family proteins induces regression of solid tumours. | journal = [[Nature (journal)|Nature]] | year=2005 | volume=435 | issue=7042 | pages=677-81 | doi=10.1038/nature03579 | pmid=15902208| bibcode=2005Natur.435..677O }}</ref> In preclinical studies utilizing [[Patient derived tumor xenografts|patient xenografts]], ABT-737 showed efficacy for treating lymphoma and other blood cancers.<ref>{{cite journal | vauthors = Hann CL, Daniel VC, Sugar EA, Dobromilskaya I, Murphy SC, Cope L, Lin X, Hierman JS, Wilburn DL, Watkins DN, Rudin CM | title = Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer | journal = Cancer Research | volume = 68 | issue = 7 | pages = 2321–8 | date = April 2008 | pmid = 18381439 | pmc = 3159963 | doi = 10.1158/0008-5472.can-07-5031 }}</ref>


Unfortunately, ABT-737 is not [[Bioavailability|bioavailable]] after [[oral administration]], leading to the development of [[navitoclax]] (ABT-263) as an orally-available derivative with similar activity on [[small cell lung cancer]] (SCLC) cell lines.<ref name="CroceReed2016"/><ref name="hauck2009">{{cite web|url=http://mct.aacrjournals.org/content/8/4/883.full.html|title=Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737|publisher=}}</ref> Navitoclax entered [[clinical trials]],<ref name="CroceReed2016"/><ref name="hauck2009"/> and showed promise in [[Tumors of the hematopoietic and lymphoid tissues|haematologic cancers]], but was stalled when it was found to cause [[thrombocytopenia]] (severe loss of platelets]], which was discovered to be caused by the platelets' requirement for Bcl-xL for survival.<ref name="CroceReed2016"/>
{{organic-compound-stub}}


Subsequently, it was reported that ABT-737 specifically induces apoptosis in senescent cells ''[[in vitro]]'' and in mouse models.<ref name=Yosef2016/>

⚫
==References==
⚫
{{reflist}}
[[Category:Chloroarenes]]
[[Category:Chloroarenes]]
[[Category:Piperazines]]
[[Category:Piperazines]]

Revision as of 17:38, 30 September 2018

ABT-737
Names
IUPAC name
4-{4-[(4’-Chloro-2-biphenylyl)methyl]-1-piperazinyl}-N-[(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)-2-butanyl]amino}-3-nitrophenyl)sulfonyl]benzamide
Identifiers
3D model (JSmol)
ChemSpider
  • InChI=1S/C42H45ClN6O5S2/c1-46(2)23-22-35(30-55-37-9-4-3-5-10-37)44-40-21-20-38(28-41(40)49(51)52)56(53,54)45-42(50)32-14-18-36(19-15-32)48-26-24-47(25-27-48)29-33-8-6-7-11-39(33)31-12-16-34(43)17-13-31/h3-21,28,35,44H,22-27,29-30H2,1-2H3,(H,45,50)/t35-/m1/s1
    Key: HPLNQCPCUACXLM-PGUFJCEWSA-N
  • InChI=1/C42H45ClN6O5S2/c1-46(2)23-22-35(30-55-37-9-4-3-5-10-37)44-40-21-20-38(28-41(40)49(51)52)56(53,54)45-42(50)32-14-18-36(19-15-32)48-26-24-47(25-27-48)29-33-8-6-7-11-39(33)31-12-16-34(43)17-13-31/h3-21,28,35,44H,22-27,29-30H2,1-2H3,(H,45,50)/t35-/m1/s1
    Key: HPLNQCPCUACXLM-PGUFJCEWBK
  • CN(C)CC[C@H](CSc1ccccc1)Nc2ccc(cc2[N+](=O)[O-])S(=O)(=O)NC(=O)c3ccc(cc3)N4CCN(CC4)Cc5ccccc5c6ccc(cc6)Cl
Properties
C42H45ClN6O5S2
Molar mass 813.43 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

ABT-737 is a small molecule drug that inhibits Bcl-2 and Bcl-xL, two members of the Bcl-2 family of evolutionarily-conserved proteins that share Bcl-2 Homology (BH) domains. First developed as a potential cancer chemotherapy,[1] it was subsequently identified as a senolytic (a drug that selectively induces cell death in senescent cells).[2]

The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion; Bcl-2 and Bcl-xL are anti-apoptotic proteins. Because many cancers have mutations in these genes that allow them to survive, scientists began working to develop drugs that would inhibit this pathway in the 1990s.[1] ABT-737 was one of the earliest of a series of drugs developed by Abbott Laboratories (now Abbvie) to target this pathway, based on their resolution of the 3D structure of Bcl-xL and studies using high-field solution nuclear magnetic resonance (NMR) that revealed how the BH domains of these proteins interacted with their targets.[1]

ABT-737 was superior to previous BCL-2 inhibitors given its higher affinity for Bcl-2, Bcl-xL and Bcl-w. In vitro studies showed that primary cells from patients with B-cell malignancies are sensitive to ABT-737.[3] In animal models, it improved survival, caused tumor regression, and cured a high percentage of mice.[4] In preclinical studies utilizing patient xenografts, ABT-737 showed efficacy for treating lymphoma and other blood cancers.[5]

Unfortunately, ABT-737 is not bioavailable after oral administration, leading to the development of navitoclax (ABT-263) as an orally-available derivative with similar activity on small cell lung cancer (SCLC) cell lines.[1][6] Navitoclax entered clinical trials,[1][6] and showed promise in haematologic cancers, but was stalled when it was found to cause thrombocytopenia (severe loss of platelets]], which was discovered to be caused by the platelets' requirement for Bcl-xL for survival.[1]

Subsequently, it was reported that ABT-737 specifically induces apoptosis in senescent cells in vitro and in mouse models.[2]

References

  1. ^ a b c d e f Croce, Carlo M; Reed, John C (October 2016). "Finally, An Apoptosis-Targeting Therapeutic for Cancer". Cancer Research. 76 (20): 5914–5920. doi:10.1158/0008-5472.CAN-16-1248. PMID 27694602. Retrieved 30 September 2018.
  2. ^ a b Yosef, Reut; Pilpel, Noam; Tokarsky-Amiel, Ronit; Biran, Anat; Ovadya, Yossi; Cohen, Snir; Vadai, Ezra; Dassa, Liat; Shahar, Elisheva; Condiotti, Reba; Ben-Porath, Ittai; Krizhanovsky, Valery (2016). "Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL". Nature Communications. 7: 11190. Bibcode:2016NatCo...711190Y. doi:10.1038/ncomms11190. PMC 4823827. PMID 27048913.
  3. ^ Vogler, Meike, et al. "Bcl-2 inhibitors: small molecules with a big impact on cancer therapy." Cell Death & Differentiation 16.3 (2008): 360–367.
  4. ^ Oltersdorf, Tilman; Elmore, Steven W.; Shoemaker, Alexander R.; Armstrong, Robert C.; Augeri, David J.; Belli, Barbara A.; Bruncko, Milan; Deckwerth, Thomas L.; Dinges, Jurgen; Hajduk, Philip J.; Joseph, Mary K.; Kitada, Shinichi; Korsmeyer, Stanley J.; Kunzer, Aaron R.; Letai, Anthony; Li, Chi; Mitten, Michael J.; Nettesheim, David G.; Ng, ShiChung; Nimmer, Paul M.; O'Connor, Jacqueline M.; Oleksijew, Anatol; Petros, Andrew M.; Reed, John C.; Shen, Wang; Tahir, Stephen K.; Thompson, Craig B.; Tomaselli, Kevin J.; Wang, Baole; Wendt, Michael D.; Zhang, Haichao; Fesik, Stephen W.; Rosenberg, Saul H. (2005). "An inhibitor of Bcl-2 family proteins induces regression of solid tumours". Nature. 435 (7042): 677–81. Bibcode:2005Natur.435..677O. doi:10.1038/nature03579. PMID 15902208.
  5. ^ Hann CL, Daniel VC, Sugar EA, Dobromilskaya I, Murphy SC, Cope L, Lin X, Hierman JS, Wilburn DL, Watkins DN, Rudin CM (April 2008). "Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer". Cancer Research. 68 (7): 2321–8. doi:10.1158/0008-5472.can-07-5031. PMC 3159963. PMID 18381439.
  6. ^ a b "Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737".
Retrieved from "https://en.wikipedia.org/w/index.php?title=ABT-737&oldid=861874925"