Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4

Tumey, L. Nathan; Boschelli, Diane H.; Bhagirath, Niala; Shim, Jaechul; Murphy, E. Angela; Goodwin, Deborah; Bennett, Eric M.; Wang, Mengmeng; Lin, Lih-Ling; Press, Barry; Shen, Marina W.H.; Frisbie, Richard K.; Morgan, Paul; Mohan, Shashi; Shin, Julia; Rao, Vikram

doi:10.1016/j.bmcl.2014.03.056

Cited by 35 publications

(34 citation statements)

References 30 publications

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“…Treatment with 5 µM IRAK1/4 inhibitor results in decreased proliferation of SEM cells, but not REH cells (Figure 4A). To avoid potential off-target effects of the IRAK1/4 inhibitor, we also used a second inhibitor named IRAK4 inhibitor compound 26, which was characterized as a more specific inhibitor of IRAK4 (Tumey et al, 2014). Treatment with 500 nM of this IRAK4 inhibitor led to an even greater inhibition of SEM cell proliferation and decreased cell viability with no detectable effect on the REH cells (Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

“…To measure the potential of IRAK inhibitors as first-line treatment, we initiated the injection of the animals with IRAK inhibitors on day 19 after transplantation, just before they succumb to leukemia. Intraperitoneal injection with IRAK1/4 inhibitor (8 mg/kg), IRAK4 inhibitor (75 mg/kg) (Tumey et al, 2014) or vehicle was performed every other day for 10 days. At sacrifice, the leukemia was confirmed by enlarged spleen, liver weights, elevated white blood cell counts (Figure S7C–E), and histological analysis.…”

Section: Resultsmentioning

confidence: 99%

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Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

Liang

Volk

Haug

et al. 2017

Cell

116

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SUMMARY Chromosomal translocations of the mixed-lineage leukemia (MLL) gene with various partner genes result in aggressive leukemia with dismal outcomes. Despite similar expression at the mRNA level from the wild-type and chimeric MLL alleles, the chimeric protein is more stable. We report that UBE2O functions in regulating the stability of wild-type MLL in response to interleukin-1 signaling. Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation and down-regulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the Super Elongation Complex. Pharmacologically inhibiting this pathway substantially delays progression and improves survival of murine leukemia through stabilizing wild-type MLL protein, which displaces the MLL chimera from some of its target genes and therefore relieves the cellular oncogenic addiction to MLL chimeras. Stabilization of MLL provides us with a paradigm in the development of therapies for aggressive MLL leukemia and perhaps for other cancers caused by translocations.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

Liang

Volk

Haug

et al. 2017

Cell

116

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“…In contrast to the scaffolding function of IRAK4, which is essential for canonical signaling pathways such as NF-kB, the kinase function of IRAK4 appears to play a minor role in canonical TLR pathways, but rather controls a subset of TLR-induced genes in a monocyte-specific way, possibly through mRNA stabilization (44,(55)(56)(57)(58). Still, inhibition of IRAK4 kinase activity in monocytes results in strongly reduced cytokine production (55,57), and an increasing number of chemically diverse, selective kinase inhibitors have been developed, several of which demonstrated in vivo efficacy in proofof-principle models (59)(60)(61)(62)(63)(64)(65)(66)(67)(68). Although most IRAK4 inhibitors showed in vivo PK properties requiring further improvement, a very recently published compound, Pf-06650833, showed remarkable in vivo potency (2.4 nM IC 50 on R848-induced peripheral blood mononuclear cells) and selectivity and has been moved forward to clinical studies (69).…”

Section: Discussionmentioning

confidence: 99%

Identification of Toll-like receptor signaling inhibitors based on selective activation of hierarchically acting signaling proteins

et al. 2018

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Toll-like receptors (TLRs) recognize various pathogen- and host tissue-derived molecules and initiate inflammatory immune responses. Exaggerated or prolonged TLR activation, however, can lead to etiologically diverse diseases, such as bacterial sepsis, metabolic and autoimmune diseases, or stroke. Despite the apparent medical need, no small-molecule drugs against TLR pathways are clinically available. This may be because of the complex signaling mechanisms of TLRs, which are governed by a series of protein-protein interactions initiated by Toll/interleukin-1 receptor homology domains (TIR) found in TLRs and the cytoplasmic adaptor proteins TIRAP and MyD88. Oligomerization of TLRs with MyD88 or TIRAP leads to the recruitment of members of the IRAK family of kinases and the E3 ubiquitin ligase TRAF6. We developed a phenotypic drug screening system based on the inducible homodimerization of either TIRAP, MyD88, or TRAF6, that ranked hits according to their hierarchy of action. From a bioactive compound library, we identified methyl-piperidino-pyrazole (MPP) as a TLR-specific inhibitor. Structure-activity relationship analysis, quantitative proteomics, protein-protein interaction assays, and cellular thermal shift assays suggested that MPP targets the TIR domain of MyD88. Chemical evolution of the original MPP scaffold generated compounds with selectivity for distinct TLRs that interfered with specific TIR interactions. Administration of an MPP analog to mice protected them from TLR4-dependent inflammation. These results validate this phenotypic screening approach and suggest that the MPP scaffold could serve as a starting point for the development of anti-inflammatory drugs.

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“…Potency loss was also observed for 27 and 28 compared with 18 and 19, albeit to a lesser extent. It was generally observed that the CHF 2 analogues offered higher intrinsic IRAK4 potency and comparable membrane permeability compared with the corresponding CF 3 analogues, as seen with (1R,2S)-cyclohexane-1,2-diamine, (1R,2S)-2-hydroxycyclohexylamine, and piperazine groups on the pyrazolopyrimidine ring (18,19,25,26,27, and 28 in Table 4). …”

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confidence: 95%

Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4

Lim

Altman

Baker

et al. 2015

ACS Med. Chem. Lett.

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Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing.

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Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4

Cited by 35 publications

References 30 publications

Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

Identification of Toll-like receptor signaling inhibitors based on selective activation of hierarchically acting signaling proteins

Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4

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