Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: Optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models

Robert L. Hudkins; James L. Diebold; Ming Tao; Kurt A. Josef; Ho Park Chung; Thelma S. Angeles; Lisa D. Aimone; Jean Husten; Mark A. Ator; Sheryl L. Meyer; Beverly P. Holskin; John T. Durkin; Alexander A. Fedorov; Elena V. Fedorov; Steven C. Almo; Joanne R. Mathiasen; Donna Bozyczko-Coyne; Michael S. Saporito; Richard W. Scott; John P. Mallamo

doi:10.1021/jm8005838

Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: Optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models

Robert L. Hudkins, James L. Diebold, Ming Tao, Kurt A. Josef, Ho Park Chung, Thelma S. Angeles, Lisa D. Aimone, Jean Husten, Mark A. Ator, Sheryl L. Meyer, Beverly P. Holskin, John T. Durkin, Alexander A. Fedorov, Elena V. Fedorov, Steven C. Almo, Joanne R. Mathiasen, Donna Bozyczko-Coyne, Michael S. Saporito, Richard W. Scott, John P. Mallamo

Biochemistry

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34 Scopus citations

Abstract

The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R² and R¹² positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.

Original language	English (US)
Pages (from-to)	5680-5689
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	18
DOIs	https://doi.org/10.1021/jm8005838
State	Published - Sep 25 2008

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Hudkins, R. L., Diebold, J. L., Tao, M., Josef, K. A., Chung, H. P., Angeles, T. S., Aimone, L. D., Husten, J., Ator, M. A., Meyer, S. L., Holskin, B. P., Durkin, J. T., Fedorov, A. A., Fedorov, E. V., Almo, S. C., Mathiasen, J. R., Bozyczko-Coyne, D., Saporito, M. S., Scott, R. W., & Mallamo, J. P. (2008). Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: Optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. Journal of Medicinal Chemistry, 51(18), 5680-5689. https://doi.org/10.1021/jm8005838

Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: Optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. / Hudkins, Robert L.; Diebold, James L.; Tao, Ming et al.
In: Journal of Medicinal Chemistry, Vol. 51, No. 18, 25.09.2008, p. 5680-5689.

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

Hudkins, RL, Diebold, JL, Tao, M, Josef, KA, Chung, HP, Angeles, TS, Aimone, LD, Husten, J, Ator, MA, Meyer, SL, Holskin, BP, Durkin, JT, Fedorov, AA, Fedorov, EV, Almo, SC, Mathiasen, JR, Bozyczko-Coyne, D, Saporito, MS, Scott, RW & Mallamo, JP 2008, 'Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: Optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models', Journal of Medicinal Chemistry, vol. 51, no. 18, pp. 5680-5689. https://doi.org/10.1021/jm8005838

Hudkins RL, Diebold JL, Tao M, Josef KA, Chung HP, Angeles TS et al. Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: Optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. Journal of Medicinal Chemistry. 2008 Sep 25;51(18):5680-5689. doi: 10.1021/jm8005838

Hudkins, Robert L. ; Diebold, James L. ; Tao, Ming et al. / Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones : Optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 18. pp. 5680-5689.

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title = "Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: Optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models",

abstract = "The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R2 and R12 positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.",

author = "Hudkins, {Robert L.} and Diebold, {James L.} and Ming Tao and Josef, {Kurt A.} and Chung, {Ho Park} and Angeles, {Thelma S.} and Aimone, {Lisa D.} and Jean Husten and Ator, {Mark A.} and Meyer, {Sheryl L.} and Holskin, {Beverly P.} and Durkin, {John T.} and Fedorov, {Alexander A.} and Fedorov, {Elena V.} and Almo, {Steven C.} and Mathiasen, {Joanne R.} and Donna Bozyczko-Coyne and Saporito, {Michael S.} and Scott, {Richard W.} and Mallamo, {John P.}",

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AU - Hudkins, Robert L.

AU - Diebold, James L.

AU - Tao, Ming

AU - Josef, Kurt A.

AU - Chung, Ho Park

AU - Angeles, Thelma S.

AU - Aimone, Lisa D.

AU - Husten, Jean

AU - Ator, Mark A.

AU - Meyer, Sheryl L.

AU - Holskin, Beverly P.

AU - Durkin, John T.

AU - Fedorov, Alexander A.

AU - Fedorov, Elena V.

AU - Almo, Steven C.

AU - Mathiasen, Joanne R.

AU - Bozyczko-Coyne, Donna

AU - Saporito, Michael S.

AU - Scott, Richard W.

AU - Mallamo, John P.

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N2 - The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R2 and R12 positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.

AB - The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R2 and R12 positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.

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Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: Optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models

Abstract

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