Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 5, 2011, Pages 1315-1319

  Dong, Qing ^a,b   Dougan, Douglas R ^a   Gong, Xianchang ^a   Halkowycz, Petro ^a   Jin, Bohan ^a   Kanouni, Toufike ^a   O'Connell, Shawn M ^a   Scorah, Nicholas ^a   Shi, Lihong ^a   Wallace, Michael B ^a   Zhou, Feng ^a  

^a Takeda San Diego Inc   (United States)

^b Shanghai Hengrui Pharmaceuticals Co Ltd   (China)

Author keywords

Allosteric; Kinase; MEK; Oncology; Pyridopyrimidinedione; SBDD

Indexed keywords

ANTINEOPLASTIC AGENT; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; TAK 733; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; BREAST CANCER; COLORECTAL CANCER; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DESIGN; DRUG STRUCTURE; DRUG SYNTHESIS; LUNG NON SMALL CELL CANCER; MELANOMA; MOUSE; NEOPLASM; NONHUMAN; PANCREAS CANCER; PROCESS OPTIMIZATION;

ANTINEOPLASTIC AGENTS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DRUG DISCOVERY; HUMANS; MAP KINASE KINASE KINASES; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NEOPLASMS; PYRIDONES; PYRIMIDINONES;

EID: 79951722555     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.01.071     Document Type: Article

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39. The fluorination step (e) was carried out on intermediate 6 prior to nitro group reduction rather than as a final step.
40. Kinase Panel: Abl1, AKT3, c-RAF, CamK1Δ, CDK2/cyclinA, cMet, cSRC, EGFR, GSK3β, IR, JAK3, P38α, PDGFRβ, PDK1, PKCα, PLK3, Syk, Tie2.
41. 2. The protein-inhibitor complex was co-purified using 200 nM of the inhibitor with recombinant MEK1 and concentrated to 16 mg/mL. Crystals were grown at 4 °C using the sitting-drop, vapor-diffusion technique. 50 nL of the protein-inhibitor complex was mixed with an equal volume of reservoir solution containing 8-12% MPD and 0.1 M MES (pH 6.0). Crystals were mounted into nylon loops, transferred into a reservoir solution supplemented with 22% ethylene glycol, and flash frozen in liquid nitrogen.
42. Compounds were administered intravenously (IV vehicle: 30% b-cyclodextrin in 0.05 M MSA) and orally (oral vehicle: 0.5% MC) at 1.4/7.8, 1.0/4.2, 0.6/2.3, and 0.5/2.0 mg/kg for mouse, rat, dog, and monkey, respectively.
43. Longer blood collection is needed to better assess bioavailability of this compound.