2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization

Harris, Christopher M.; Ericsson, Anna; Argiriadi, M.A.; Barberis, Claude; Borhani, David W.; Burchat, Andrew; Calderwood, David J.; Cunha, George A.; Dixon, R. W.; Frank, Kristine E.; Johnson, Eric F.; Kamens, Joanne; Kwak, Silvia; Li, Biqin; Mullen, Kelly; Perron, Denise; Wang, Lu; Wishart, Neil; Wu, Xia; Zhang, Xiaolei; Zmetra, Tami R.; Talanian, Robert V.

doi:10.1016/j.bmcl.2009.10.103

Cited by 20 publications

(11 citation statements)

References 8 publications

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“…In the last decade, several secondary metabolite compounds were isolated that inhibit MK-2 (23,67). Recently developed synthetic compounds include a series of derivatives of pyrrole, furan, thiophen, oxazole, thiazole, triazole, and imidazole compounds (Pharmacia) (65), undisclosed compounds (Schering/Bayer) (26), benzopyranopyridine-type compounds (15), 2,4-diaminopyrimidine-type compounds (Abbott Laboratories) (7,24), and various aminocyanopyridine-type (2), ␤-carboline-type (63), pyrrolopyridine-type (which includes C23), and benzothiophene-type compounds (Pfizer) (3)(4)(5)41). Some of these compounds inhibit MK-2 with K i values in the nanomolar range.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury

Pengal

Guess

Agrawal

et al. 2011

American Journal of Physiology-Renal Physiology

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While mitogen-activated protein kinase (MAPK) activation has been implicated in the pathogenesis of various glomerular diseases, including nephrotic syndrome (NS), its specific role in podocyte injury is not known. We hypothesized that MK-2, a downstream substrate of p38 MAPK, mediates the adverse effects of this pathway and that inhibition of MK-2 would protect podocytes from NS-related injury. Using cultured podocytes, we analyzed 1) the roles of MK-2 and p38 MAPK in puromycin aminonucleoside (PAN)-induced podocyte injury; 2) the ability of specific MK-2 and p38 MAPK inhibitors to protect podocytes against injury; 3) the role of serum albumin, known to induce podocyte injury, in activating p38 MAPK/MK-2 signaling; and 4) the role of p38 MAPK/MK-2 signaling in the expression of Cox-2, an enzyme associated with podocyte injury. Treatment with protein kinase inhibitors specific for both MK-2 (C23, a pyrrolopyridine-type compound) or p38 MAPK (SB203580) reduced PAN-induced podocyte injury and actin cytoskeletal disruption. Both inhibitors reduced baseline podocyte p38 MAPK/MK-2 signaling, as measured by the degree of phosphorylation of HSPB1, a downstream substrate of MK-2, but exhibited disparate effects on upstream signaling. Serum albumin activated p38 MAPK/MK-2 signaling and induced Cox-2 expression, and these responses were blocked by both inhibitors. Given the critical importance of podocyte injury to both NS and other progressive glomerular diseases, these data suggest an important role for p38 MAPK/MK-2 signaling in podocyte injury and identify MK-2 inhibition as a promising potential therapeutic strategy to protect podocytes in various glomerular diseases.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury

Pengal

Guess

Agrawal

et al. 2011

American Journal of Physiology-Renal Physiology

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“…A number of regions in the original scaffold 5 were altered, including exchange of the labile phenol group for an indazole bioisostere 6 ( Figure 5.5). [64]. By varying substituents at the 3-and 7-indazole positions of 6, IC 50 values increased from 24 µM (6a: R 1 = R 2 = H) to 1.6 and 0.16 µM for 2-benzothiophene derivatives, 6b and 6c, respectively.…”

Section: Inhibition Of P38 In Werner Syndromementioning

confidence: 96%

“…The structure-based design of new MK2 inhibitors that target TNF-α production have also been carried out by Abbott Laboratories (IL, USA) [63,64]. Preliminary studies examined the binding of 2,4-diaminopyrimidines to the MK2 protein hinge region using protein crystallographic data and this provided considerable insight into inhibitor binding modes, as well as H-bonding interactions that could be exploited to potentially increase potency and selectivity [63].…”

Section: Inhibition Of P38 In Werner Syndromementioning

confidence: 98%

Microwave-assisted synthesis of MK2 inhibitors for targeting p38 MAPK signal transduction in Werner syndrome cells

Bagley

Baashen

Jessica

et al. 2014

Microwaves in Drug Discovery and Development: Recent Advances

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“…Structural optimization of 2.15 leads to indazole-pyrrolo [3,2-d] pyrimidines such as 2.16 [61], endowed with strong cell-free potency on MK2, and on LPS-stimulated TNFa release. The selectivity of 2.16 and of its analogs vs. other kinases is good.…”

Section: Hsp27mentioning

confidence: 99%

“…The selectivity of 2.16 and of its analogs vs. other kinases is good. Compound 2.16 has a poor pharmacokinetic (PK) profile in rats by oral administration [61].…”

Section: Hsp27mentioning

confidence: 99%

Targeting the Protein Quality Control (PQC) Machinery

Seneci

2015

Chemical Modulators of Protein Misfolding and Neurodegenerative Disease

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2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization

Cited by 20 publications

References 8 publications

Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury

Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury

Microwave-assisted synthesis of MK2 inhibitors for targeting p38 MAPK signal transduction in Werner syndrome cells

Targeting the Protein Quality Control (PQC) Machinery

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