2,3-Substituted quinoxalin-6-amine analogs as antiproliferatives: A structure–activity relationship study

Chen, Qianyi; Bryant, Vashti C.; Lopez, Hernando; Kelly, David L.; Luo, Xu; Natarajan, Amarnath

doi:10.1016/j.bmcl.2011.02.055

Cited by 32 publications

(17 citation statements)

References 19 publications

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“…The quinoxaline urea analog 13-197 was synthesized and purified (> 98%) as previously described (25, 26). Efavirenz (EFV) was obtained from Hetero Labs Ltd. (Hyderabad, India).…”

Section: Methodsmentioning

confidence: 99%

Targeting the NF-κB and mTOR Pathways with a Quinoxaline Urea Analog That Inhibits IKKβ for Pancreas Cancer Therapy

Radhakrishnan

Bryant

Blowers

et al. 2013

Clinical Cancer Research

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Purpose The presence of TNFα in ~ 50% of surgically resected tumors suggests that the canonical NF-κB and the mTOR pathways are activated. IκB kinase β (IKKβ) acts as the signaling node that regulates transcription via the p-IκBα/NF-κB axis and regulates translation via the mTOR/p-S6K/p-eIF4EBP axis. A kinome screen identified a quinoxaline urea analog 13-197 as an IKKβ inhibitor. We hypothesized that targeting the NF-κB and mTOR pathways with 13-197 will be effective in malignancies driven by these pathways. Experimental Design Retrospective clinical and preclinical studies in pancreas cancers have implicated NF-κB. We examined the effects of 13-197, on the downstream targets of the NF-κB and mTOR pathways in pancreatic cancer cells, pharmacokinetics, toxicity and tumor growth and metastases in vivo. Results 13-197 inhibited the kinase activity of IKKβ in vitro and TNFα mediated NF-κB transcription in cells with low-μM potency. 13-197 inhibited the phosphorylation of IκBα, S6K and eIF4EBP, induced G1 arrest and down regulated the expression of antiapoptotic proteins in pancreatic cancer cells. Prolonged administration of 13-197 did not induce granulocytosis and protected mice from LPS-induced death. Results also show that 13-197 is orally available with extensive distribution to peripheral tissues and inhibited tumor growth and metastasis in an orthotopic pancreatic cancer model without any detectable toxicity. Conclusion These results suggest that 13-197 targets IKKβ and thereby inhibits mTOR and NF-κB pathways. Oral availability along with in vivo efficacy without obvious toxicities makes this quinoxaline urea chemotype, a viable cancer therapeutic.

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“…The quinoxaline urea analog 13-197 was synthesized and purified (> 98%) as previously described (25, 26). Efavirenz (EFV) was obtained from Hetero Labs Ltd. (Hyderabad, India).…”

Section: Methodsmentioning

confidence: 99%

Targeting the NF-κB and mTOR Pathways with a Quinoxaline Urea Analog That Inhibits IKKβ for Pancreas Cancer Therapy

Radhakrishnan

Bryant

Blowers

et al. 2013

Clinical Cancer Research

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“…Synthesis and screening of a focused library of quinoxaline compounds led to a well-defined structure activity relationship and the identification of a quinoxaline urea analog that inhibited growth of cancer cells with low micromolar potency (35, 36). Recent studies by us also suggest that the quinoxaline urea analog 13–197 inhibits the constitutively active form of IKKβ which is an emerging target for therapeutic development (28–30).…”

Section: Introductionmentioning

confidence: 99%

Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

Chaturvedi

Rajule

Shukla

et al. 2013

Molecular Cancer Therapeutics

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Mantle cell lymphoma (MCL) is one of the most aggressive B cell non-Hodgkin lymphomas with a median survival of about five years. Currently, there is no curative therapy available for refractory MCL because of relapse from therapy-resistant tumor cells. The NF-κB and mTOR pathways are constitutively active in refractory MCL leading to increased proliferation and survival. Targeting these pathways is an ideal strategy to improve therapy for refractory MCL. Therefore, we investigated the in vitro and in vivo antilymphoma activity and associated molecular mechanism of action of a novel compound 13-197, a quinoxaline analog that specifically perturbs IκB kinase (IKK) β, a key regulator of the NF-κB pathway. 13-197 decreased the proliferation and induced apoptosis in MCL cells including therapy-resistant cells compared to control cells. Furthermore, we observed down-regulation of IκBα phosphorylation and inhibition of NF-κB nuclear translocation by 13-197 in MCL cells. In addition, NF-κB regulated genes such as cyclin D1, Bcl-XL and Mcl-1 were down-regulated in 13-197-treated cells. 13-197 also inhibited the phosphorylation of S6K and 4E-BP1, the downstream molecules of mTOR pathway that are also activated in refractory MCL. Further, 13-197 reduced the tumor burden in vivo in the kidney, liver, and lungs of therapy-resistant MCL bearing NOD-SCID mice compared to vehicle treated mice; indeed, 13-197 significantly increased the survival of MCL transplanted mice. Together, results suggest that 13-197 as a single agent disrupts the NF-κB and mTOR pathways leading suppression of proliferation and increased apoptosis in malignant MCL cells including reduction in tumor burden in mice.

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“…Several biological effects have been reported, including anticancer (14,16,17), antimicrobial (18)(19)(20)(21)(22), antiviral (23), and anti-inflammatory and antioxidant (24,25) effects.…”

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confidence: 99%

In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

Kaplum

Cogo

Sangi

et al. 2016

Antimicrob Agents Chemother

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Leishmaniasis is endemic in 98 countries and territories worldwide. The therapies available for leishmaniasis have serious side effects, thus prompting the search for new therapies. The present study investigated the antileishmanial activities of 2,3-diarylsubstituted quinoxaline derivatives against Leishmania amazonensis. The antiproliferative activities of 6,7-dichloro-2,3-diphenylquinoxaline (LSPN329) and 2,3-di-(4-methoxyphenyl)-quinoxaline (LSPN331) against promastigotes and intracellular amastigotes were assessed, and the cytotoxicities of LSPN329 and LSPN331 were determined. Morphological and ultrastructural alterations were examined by electron microscopy, and biochemical alterations, reflected by the mitochondrial membrane potential (⌬⌿m), mitochondrial superoxide anion (O 2 · ؊ ) concentration, the intracellular ATP concentration, cell volume, the level of phosphatidylserine exposure on the cell membrane, cell membrane integrity, and lipid inclusions, were evaluated. In vivo antileishmanial activity was evaluated in a murine cutaneous leishmaniasis model. Compounds LSPN329 and LSPN331 showed significant selectivity for promastigotes and intracellular amastigotes and low cytotoxicity. In promastigotes, ultrastructural alterations were observed, including an increase in lipid inclusions, concentric membranes, and intense mitochondrial swelling, which were associated with hyperpolarization of ⌬⌿m, an increase in the O 2 · ؊ concentration, decreased intracellular ATP levels, and a decrease in cell volume. Phosphatidylserine exposure and DNA fragmentation were not observed. The cellular membrane remained intact after treatment. Thus, the multifactorial response that was responsible for the cellular collapse of promastigotes was based on intense mitochondrial alterations. BALB/c mice treated with LSPN329 or LSPN331 showed a significant decrease in lesion thickness in the infected footpad. Therefore, the antileishmanial activity and mitochondrial mechanism of action of LSPN329 and LSPN331 and the decrease in lesion thickness in vivo brought about by LSPN329 and LSPN331 make them potential candidates for new drug development for the treatment of leishmaniasis.

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2,3-Substituted quinoxalin-6-amine analogs as antiproliferatives: A structure–activity relationship study

Cited by 32 publications

References 19 publications

Targeting the NF-κB and mTOR Pathways with a Quinoxaline Urea Analog That Inhibits IKKβ for Pancreas Cancer Therapy

Targeting the NF-κB and mTOR Pathways with a Quinoxaline Urea Analog That Inhibits IKKβ for Pancreas Cancer Therapy

Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis

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