View source for ABT-737

{{short description|Chemical compound}}
{{cs1 config|name-list-style=vanc}}
{{Chembox
| ImageFile = ABT-737.svg
| ImageSize = 200px
| PIN = 4-{4-[(4′-Chloro[1,1′-biphenyl]-2-yl)methyl]piperazin-1-yl}-''N''-(4-{[(2''R'')-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzene-1-sulfonyl)benzamide
| OtherNames =
| Section1 = {{Chembox Identifiers
|  CASNo = 852808-04-9
|  CASNo_Ref = {{cascite|correct|CAS}}
|  UNII_Ref = {{fdacite|correct|FDA}}
|  UNII = Z5NFR173NV
|  PubChem = 11228183
|  ChEBI = 47575
|  ChemSpiderID = 9403232
|  SMILES = CN(C)CC[C@H](CSc1ccccc1)Nc2ccc(cc2[N+](=O)[O-])S(=O)(=O)NC(=O)c3ccc(cc3)N4CCN(CC4)Cc5ccccc5c6ccc(cc6)Cl
|  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
|  InChIKey = HPLNQCPCUACXLM-PGUFJCEWBK
|  StdInChI = 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
|  StdInChIKey = HPLNQCPCUACXLM-PGUFJCEWSA-N
}}
| Section2 = {{Chembox Properties
|  C=42|H=45|Cl=1|N=6|O=5|S=2
|  Appearance =
|  Density =
|  MeltingPt =
|  BoilingPt =
|  Solubility =
}}
| Section3 = {{Chembox Hazards
|  MainHazards =
|  FlashPt =
|  Autoignition =
}}
}}
'''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 |pmc=5117672 |url=}}</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 |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"/>
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 | s2cid=4335635 }}</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 journal |vauthors=Hauck P, Chao BH, Litz J, Krystal GW |title=Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737 |journal=Mol Cancer Ther |date=April 2009 |volume=8 |issue=4 |pages=883–92 |doi=10.1158/1535-7163.MCT-08-1118 |pmid=19372561 |url=https://mct.aacrjournals.org/content/8/4/883 |accessdate=9 September 2019|doi-access= |s2cid=19245418 }}</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"/>
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:4-Chlorophenyl compounds]]
[[Category:Piperazines]]
[[Category:Sulfonamides]]
[[Category:Drugs developed by AbbVie]]
[[Category:Thioethers]]