Synthesis and Evaluation of Phosphorus Containing, Specific CDK9/CycT1 Inhibitors

Németh, Gábor; Greff, Zoltán; Sipos, Andrea; Varga, Zoltán; Székely, Rita; Sebestyén, Mónika; Jászay, Zsuzsa M.; Béni, Szabolcs; Nemes, Zoltán; Pirat, Jean‐Luc; Volle, J.‐N.; Virieux, David; Gyuris, Ágnes; Kelemenics, K.; Ay, Eva; Minárovits, János; Szathmáry, Susan; Kéri, Gÿorgý; Őrfi, László

doi:10.1021/jm401742r

Cited by 65 publications

(33 citation statements)

References 39 publications

(124 reference statements)

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“…After the reaction mixture was stirred overnight, the solution was concentrated in vacuo to produce compound 6 and then was used without further purification. 24 To a stirred solution of n –BuLi (6.11 mL, 15.2 mmol) in toluene at –78 °C, dimethyl methylphosphonate (1.69 mL, 15.2 mmol) was added dropwise. The resulting solution was allowed to stir for 30 minutes and then acid chloride 6 (3.11 mmol) was added dropwise.…”

Section: Methodsmentioning

confidence: 99%

Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism

et al. 2017

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Butyrophilin 3A1 (BTN3A1) binds small phosphorous-containing molecules, which initiates transmembrane signaling and activates butyrophilin-responsive cells. We synthesized several phosphinophosphonates and their corresponding tris-pivaloyloxymethyl prodrugs and examined their effects on BTN3A1. An analog of (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) bound to BTN3A1 with intermediate affinity, which was enthalpy-driven. Docking studies revealed binding to the basic surface pocket and interactions between the allylic hydroxyl group and the BTN3A1 backbone. The phosphinophosphonate stimulated proliferation of Vγ9Vδ2 T cells with moderate activity (EC50 = 26 µM). Cellular potency was enhanced >600-fold in the tris-POM prodrug (EC50 = 0.041 µM). The novel prodrug also induced T cell mediated leukemia cell lysis. Analysis of dose response data reveals HMBPP-induced Hill coefficients of 0.69 for target cell lysis and 0.68 in interferon secretion. Together, tris-POM prodrugs enhance the cellular activity of phosphinophosphonates, reveal structure-activity relationships of butyrophilin ligands, and support a negatively cooperative model of cellular butyrophilin activation.

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Section: Methodsmentioning

confidence: 99%

Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism

et al. 2017

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“…Of note, the phosphinic acid #93 was shown to be the most specific ATP-competitive inhibitor of CDK9/cyclin T1 kinase activity with an IC 50 of 142 nM (Nemeth et al 2014). This compound appeared to have some antiviral activity in one HIV-1 proliferation assay in MT4 cells even though further validation tests should be performed to ascertain efficacy against HIV in more relevant HIV-infected models.…”

Section: Inhibition Of P-tefb An Essential Cellular Complex For Himentioning

confidence: 99%

Targeting HIV Transcription: The Quest for a Functional Cure

Mousseau

Mediouni

Valente

2015

The Future of HIV-1 Therapeutics

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Antiretroviral therapy (ART) potently suppresses HIV-1 replication, but the virus persists in quiescent infected CD4+T cells as a latent integrated provirus, and patients must indefinitely remain on therapy. If ART is terminated, these integrated proviruses can reactivate, driving new rounds of infection. A functional cure for HIV requires eliminating low-level ongoing viral replication that persists in certain tissue sanctuaries and preventing viral reactivation. The HIV Tat protein plays an essential role in HIV transcription by recruiting the kinase activity of the P-TEFb complex to the viral mRNA’s stem–bulge–loop structure, TAR, activating transcriptional elongation. Because the Tat-mediated transactivation cascade is critical for robust HIV replication, the Tat/TAR/P-TEFb complex is one of the most attractive targets for drug development. Importantly, compounds that interfere with transcription could impair viral reactivation, low-level ongoing replication, and replenishment of the latent reservoir, thereby reducing the size of the latent reservoir pool. Here, we discuss the potential importance of transcriptional inhibitors in the treatment of latent HIV-1 disease and review recent findings on targeting Tat, TAR, and P-TEFb individually or as part of a complex. Finally, we discuss the impact of extracellular Tat in HIV-associated neurocognitive disorders and cancers.

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“…The mono methyl ester mono acid chloride 8 then could be obtained by reaction with oxalyl chloride in DMF. 15 In principal, reaction of this acid chloride with any alcohol should afford a mixed diester. However, out of concern for the lability of an allylic ester like that derived from geraniol, 16 S-(−)-citronellol was employed to provide the mixed ester 9 .…”

Section: Synthesismentioning

confidence: 99%

A new motif for inhibitors of geranylgeranyl diphosphate synthase

Foust

Allen

Holstein

et al. 2016

Bioorganic & Medicinal Chemistry

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The enzyme geranylgeranyl diphosphate synthase (GGDPS) is believed to receive the substrate farnesyl diphosphate through one lipophilic channel and release the product geranylgeranyl diphosphate through another. Bisphosphonates with two isoprenoid chains positioned on the α-carbon have proven to be effective inhibitors of this enzyme. Now a new motif has been prepared with one isoprenoid chain on the α-carbon, a second included as a phosphonate ester, and the potential for a third at the α-carbon. The pivaloyloxymethyl prodrugs of several compounds based on this motif have been prepared and the resulting compounds have been tested for their ability to disrupt protein geranylgeranylation and induce cytotoxicity in myeloma cells. The initial biological studies reveal activity consistent with GGDPS inhibition, and demonstrate a structure-function relationship which is dependent on the nature of the alkyl group at the α-carbon.

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Synthesis and Evaluation of Phosphorus Containing, Specific CDK9/CycT1 Inhibitors

Cited by 65 publications

References 39 publications

Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism

Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism

Targeting HIV Transcription: The Quest for a Functional Cure

A new motif for inhibitors of geranylgeranyl diphosphate synthase

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