Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).

D Niculescu-Duvaz; C Gaulon; HP Dijkstra; I Niculescu-Duvaz; A Zambon; D Ménard; BM Suijkerbuijk; A Nourry; L Davies; H Manne; F Friedlos; L Ogilvie; CJ Springer

doi:10.1021/jm801509w

Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).

D Niculescu-Duvaz, C Gaulon, HP Dijkstra, I Niculescu-Duvaz, A Zambon, D Ménard, BM Suijkerbuijk, A Nourry, L Davies, H Manne, F Friedlos, L Ogilvie, CJ Springer

Cancer Research UK Manchester Institute

Research output: Contribution to journal › Article › peer-review

Abstract

BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50−70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas.

Original language	English
Pages (from-to)	2255-2264
Number of pages	10
Journal	Journal of Medicinal Chemistry
DOIs	https://doi.org/10.1021/jm801509w
Publication status	Published - Apr 2009

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Manchester Cancer Research Centre

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Niculescu-Duvaz, D., Gaulon, C., Dijkstra, HP., Niculescu-Duvaz, I., Zambon, A., Ménard, D., Suijkerbuijk, BM., Nourry, A., Davies, L., Manne, H., Friedlos, F., Ogilvie, L., & Springer, CJ. (2009). Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF). Journal of Medicinal Chemistry, 2255-2264. https://doi.org/10.1021/jm801509w

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title = "Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).",

abstract = "BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50−70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas.",

author = "D Niculescu-Duvaz and C Gaulon and HP Dijkstra and I Niculescu-Duvaz and A Zambon and D M{\'e}nard and BM Suijkerbuijk and A Nourry and L Davies and H Manne and F Friedlos and L Ogilvie and CJ Springer",

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doi = "10.1021/jm801509w",

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Niculescu-Duvaz, D, Gaulon, C, Dijkstra, HP, Niculescu-Duvaz, I, Zambon, A, Ménard, D, Suijkerbuijk, BM, Nourry, A, Davies, L, Manne, H, Friedlos, F, Ogilvie, L & Springer, CJ 2009, 'Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).', Journal of Medicinal Chemistry, pp. 2255-2264. https://doi.org/10.1021/jm801509w

TY - JOUR

T1 - Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).

AU - Niculescu-Duvaz, D

AU - Gaulon, C

AU - Dijkstra, HP

AU - Niculescu-Duvaz, I

AU - Zambon, A

AU - Ménard, D

AU - Suijkerbuijk, BM

AU - Nourry, A

AU - Davies, L

AU - Manne, H

AU - Friedlos, F

AU - Ogilvie, L

AU - Springer, CJ

PY - 2009/4

Y1 - 2009/4

N2 - BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50−70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas.

AB - BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50−70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas.

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U2 - 10.1021/jm801509w

DO - 10.1021/jm801509w

M3 - Article

C2 - 19323560

SN - 0022-2623

SP - 2255

EP - 2264

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

ER -

Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).

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