Discovery of CYT997: a structurally novel orally active microtubule targeting agent

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 16, 2009, Pages 4639-4642

  Burns, Christopher J ^a   Harte, Michael F ^a   Bu, Xianyong ^a   Fantino, Emmanuelle ^a   Joffe, Max ^a   Sikanyika, Harrison ^a   Su, Stephen ^a   Tranberg, C Elisabet ^a   Wilson, Neil ^a   Charman, Susan A ^b   Shackleford, David M ^b   Wilks, Andrew F ^a  

^a Cytopia Ltd   (Australia)

^b MONASH UNIVERSITY   (Australia)

Author keywords

Microtubule disruptor; Pyrimidine; Tubulin polymerization inhibitor

Indexed keywords

ALKYL GROUP; ANTINEOPLASTIC AGENT; CYT 997; FUNCTIONAL GROUP; TUBULIN POLYMERIZATION INHIBITOR; UNCLASSIFIED DRUG; VASCULAR TARGETING AGENT;

ARTICLE; CANCER CELL; CELL CYCLE ARREST; CELL CYCLE G2 PHASE; CELL CYCLE M PHASE; CONTROLLED STUDY; CYTOTOXICITY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; ENANTIOMER; GLUCURONIDATION; MAXIMUM PLASMA CONCENTRATION; MICROTUBULE ASSEMBLY; NONHUMAN; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

ADMINISTRATION, ORAL; ANIMALS; CELL LINE, TUMOR; DRUG DISCOVERY; HUMANS; MICROTUBULES; PYRIDINES; PYRIMIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TUBULIN MODULATORS;

EID: 67651112008     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.06.079     Document Type: Article

References (19)

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5. 2. Cell proliferation was assessed using Alamar Blue™ (Serotec).
6. 2) using microtubules purified from bovine brain. Glycerol (5%) and GTP (1 mM) were added to the tubulin mixture before the addition of 19 in order to promote polymerization. In the case of the negative control no GTP was added. The assay was commenced by addition of 10 μL of 19 (3 μM in 1% DMSO) to 100 μL of the tubulin reaction mixture (∼72 μg tubulin/reaction) in a pre-warmed 96-well plate. Absorbance was read every 60 s at a wavelength of 340 nm for a period of 40 min using a BMG Polarstar plate reader at 37 °C.
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8. Burns, C. J.; Fantino, E.; Phillips, I. D.; Su, S.; Harte, M. F.; Bukczynska, P. E.; Dublevic, V.; Frazzetto, M.; Joffe, M.; Kruszelnicki, I.; Wang, B.; Wang, Y.; Wilson, N.; Dilley, R. J.; Wan, S.; Charman, S. A.; Shackleford, D. M.; Fida, R.; Malcontenti-Wilson, C.; Christophi, C.; Wilks, A. F., submitted for publication.
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15. 3, 300 MHz) δ 0.99 (t, J 7.2 Hz, 3H), 1.19 (t, J 7.2 Hz, 3H), 1.36-1.53 (m, 2H), 1.83-2.05 (m, 2H), 2.11 (d, J 0.9 Hz, 3H), 3.28-3.37 (m, 2H), 3.92 (s, 3H), 4.63 (t, J 4.8 Hz, 1H), 4.77 (d, J 6.6 Hz, 1H), 5.29-5.36 (m, 1H), 6.83 (br s, 1H), 7.22-7.26 (m, 1H), 7.68 (dt, J 7.8, 1.8 Hz, 1H), 7.72 (d, J 1.8 Hz, 1H), 7.86 (dd, J 8.7, 1.8 Hz, 1H), 8.06 (s, 1H), 8.07 (d, J 8.7 Hz, 1H), 8.47 (dd, J 5.5, 1.8 Hz, 1H), 8.69 (d, J 2.1 Hz, 1H).
16. The S amine 28 was obtained with an ee of 80%.
17. We required multi-kilogram amounts of 24 to support clinical trials. However, the asymmetric reduction of 26 and conversion to amine 28 via the azide was not considered viable on large scale. Therefore, we obtained the S amine 28 in bulk quantities as its racemate and resolved it into its pure enantiomer through salt formation with mandelic acid.
18. Phase I dose-escalation study for CYT997. ACTR number: ACTRN12605000793617. www.anzctr.com.au
19. Phase I accelerated dose-escalation study of CYT997 given as an oral capsule every two weeks in patients with advanced solid tumours. ACTR number: ACTRN12606000520538. www.anzctr.com.au