Alisertib

Alisertib
Names
	Preferred IUPAC name 4-{[9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid
Identifiers
CAS Number	1028486-01-2;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:125628;
ChEMBL	ChEMBL483158;
ChemSpider	24700147;
IUPHAR/BPS	7790;
KEGG	D10085;
PubChem CID	24771867;
UNII	T66ES73M18;
CompTox Dashboard (EPA)	DTXSID30145539 ;
	InChI InChI=1S/C27H20ClFN4O4/c1-36-21-5-3-4-20(29)23(21)25-19-10-15(28)6-8-17(19)24-14(12-30-25)13-31-27(33-24)32-16-7-9-18(26(34)35)22(11-16)37-2/h3-11,13H,12H2,1-2H3,(H,34,35)(H,31,32,33) Key: ZLHFILGSQDJULK-UHFFFAOYSA-N; InChI=1/C27H20ClFN4O4/c1-36-21-5-3-4-20(29)23(21)25-19-10-15(28)6-8-17(19)24-14(12-30-25)13-31-27(33-24)32-16-7-9-18(26(34)35)22(11-16)37-2/h3-11,13H,12H2,1-2H3,(H,34,35)(H,31,32,33) Key: ZLHFILGSQDJULK-UHFFFAOYAB;
	SMILES COC1=C(C(=CC=C1)F)C2=NCC3=CN=C(N=C3C4=C2C=C(C=C4)Cl)NC5=CC(=C(C=C5)C(=O)O)OC;
Properties
Chemical formula	C27H20ClFN4O4
Molar mass	518.93 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Alisertib (MLN8237) is an orally available , investigational, reversible, ATP-competitive, selective aurora A kinase inhibitor developed by Takeda.^[1] Inhibition of aurora A kinase A leads to disruption of mitotic spindle apparatus assembly, disruption of chromosome segregation, and inhibition of cell proliferation.^[2]^[3]

Takeda investigated alisertib as a treatment for relapsed or refractory peripheral T-cell lymphoma^[4]^[5] and development was paused in 2015^[6] until Puma Biotechnology licensed global rights to alisertib from Takeda in 2022.^[7]^[8]

In clinical trials to date, alisertib has shown single agent activity and activity in combination with other cancer drugs in the treatment of many different types of cancers, including hormone receptor positive breast cancer, triple negative breast cancer, small cell lung cancer and head and neck cancer.^[9]

References

^ Friedberg, JW; Mahadevan, D; Cebula, E; Persky, D; Lossos, I; Agarwal, AB; Jung, J; Burack, R; Zhou, X; Leonard, EJ; Fingert, H; Danaee, H; Bernstein, SH (Jan 1, 2014). "Phase II study of alisertib, a selective Aurora A kinase inhibitor, in relapsed and refractory aggressive B- and T-cell non-Hodgkin lymphomas". Journal of Clinical Oncology. 32 (1): 44–50. doi:10.1200/JCO.2012.46.8793. PMC 3867644. PMID 24043741.
^ Manfredi, Mark G.; Ecsedy, Jeffrey A.; Chakravarty, Arijit; Silverman, Lee; Zhang, Mengkun; Hoar, Kara M.; Stroud, Stephen G.; Chen, Wei; Shinde, Vaishali; Huck, Jessica J.; Wysong, Deborah R.; Janowick, David A.; Hyer, Marc L.; Leroy, Patrick J.; Gershman, Rachel E. (2011-12-15). "Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays". Clinical Cancer Research. 17 (24): 7614–7624. doi:10.1158/1078-0432.CCR-11-1536. ISSN 1557-3265. PMID 22016509.
^ Niu, Huifeng; Manfredi, Mark; Ecsedy, Jeffrey A. (2015-08-24). "Scientific Rationale Supporting the Clinical Development Strategy for the Investigational Aurora A Kinase Inhibitor Alisertib in Cancer". Frontiers in Oncology. 5: 189. doi:10.3389/fonc.2015.00189. ISSN 2234-943X. PMC 4547019. PMID 26380220.
^ "Millennium Initiates Pivotal Phase 3 Trial of MLN8237 in Patients With Relapsed or Refractory Peripheral T-cell Lymphoma". Takeda Pharmaceutical Company Limited; Millennium Pharmaceuticals, Inc. March 6, 2012. Retrieved 20 March 2014.
^ "Research and Development Pipeline (As of February 5, 2014)" (PDF). Takeda Pharmaceutical Company Limited. February 5, 2014. p. 2. Retrieved 20 March 2014.
^ "Takeda Announces Termination of Alisertib Phase 3 Trial in Relapsed or Refractory Peripheral T-cell Lymphoma".
^ Taylor, Nick Paul (September 21, 2022). "Puma pounces on failed Takeda drug, snapping up cancer prospect for knockdown price".
^ Taylor, Phil (September 21, 2022). "Takeda farms out cancer drug alisertib to Puma Biotech".
^ Melichar, Bohuslav; Adenis, Antoine; Lockhart, A. Craig; Bennouna, Jaafar; Dees, E. Claire; Kayaleh, Omar; Obermannova, Radka; DeMichele, Angela; Zatloukal, Petr; Zhang, Bin; Ullmann, Claudio Dansky; Schusterbauer, Claudia (April 2015). "Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study". The Lancet. Oncology. 16 (4): 395–405. doi:10.1016/S1470-2045(15)70051-3. ISSN 1474-5488. PMID 25728526.

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[1] Friedberg, JW; Mahadevan, D; Cebula, E; Persky, D; Lossos, I; Agarwal, AB; Jung, J; Burack, R; Zhou, X; Leonard, EJ; Fingert, H; Danaee, H; Bernstein, SH (Jan 1, 2014). "Phase II study of alisertib, a selective Aurora A kinase inhibitor, in relapsed and refractory aggressive B- and T-cell non-Hodgkin lymphomas". Journal of Clinical Oncology. 32 (1): 44–50. doi:10.1200/JCO.2012.46.8793. PMC 3867644. PMID 24043741.

[2] Manfredi, Mark G.; Ecsedy, Jeffrey A.; Chakravarty, Arijit; Silverman, Lee; Zhang, Mengkun; Hoar, Kara M.; Stroud, Stephen G.; Chen, Wei; Shinde, Vaishali; Huck, Jessica J.; Wysong, Deborah R.; Janowick, David A.; Hyer, Marc L.; Leroy, Patrick J.; Gershman, Rachel E. (2011-12-15). "Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays". Clinical Cancer Research. 17 (24): 7614–7624. doi:10.1158/1078-0432.CCR-11-1536. ISSN 1557-3265. PMID 22016509.

[3] Niu, Huifeng; Manfredi, Mark; Ecsedy, Jeffrey A. (2015-08-24). "Scientific Rationale Supporting the Clinical Development Strategy for the Investigational Aurora A Kinase Inhibitor Alisertib in Cancer". Frontiers in Oncology. 5: 189. doi:10.3389/fonc.2015.00189. ISSN 2234-943X. PMC 4547019. PMID 26380220.

[4] "Millennium Initiates Pivotal Phase 3 Trial of MLN8237 in Patients With Relapsed or Refractory Peripheral T-cell Lymphoma". Takeda Pharmaceutical Company Limited; Millennium Pharmaceuticals, Inc. March 6, 2012. Retrieved 20 March 2014.

[5] "Research and Development Pipeline (As of February 5, 2014)" (PDF). Takeda Pharmaceutical Company Limited. February 5, 2014. p. 2. Retrieved 20 March 2014.

[6] "Takeda Announces Termination of Alisertib Phase 3 Trial in Relapsed or Refractory Peripheral T-cell Lymphoma".

[7] Taylor, Nick Paul (September 21, 2022). "Puma pounces on failed Takeda drug, snapping up cancer prospect for knockdown price".

[8] Taylor, Phil (September 21, 2022). "Takeda farms out cancer drug alisertib to Puma Biotech".

[9] Melichar, Bohuslav; Adenis, Antoine; Lockhart, A. Craig; Bennouna, Jaafar; Dees, E. Claire; Kayaleh, Omar; Obermannova, Radka; DeMichele, Angela; Zatloukal, Petr; Zhang, Bin; Ullmann, Claudio Dansky; Schusterbauer, Claudia (April 2015). "Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study". The Lancet. Oncology. 16 (4): 395–405. doi:10.1016/S1470-2045(15)70051-3. ISSN 1474-5488. PMID 25728526.

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