Synthesis and biological evaluation of novel quinazoline-4-piperidinesulfamide derivatives as inhibitors of NPP1

Forcellini, Elsa; Boutin, Sophie; Lefebvre, Carole-Anne; Shayhidin, Elnur Elyar; Boulanger, Marie-Chloé; Rhéaume, Gabrielle; Barbeau, Xavier; Lagüe, Patrick; Mathieu, Patrick; Paquin, Jean‐François

doi:10.1016/j.ejmech.2018.01.094

“…Raloxifene is an FDA-approved selective estrogen receptor modulator used in the prevention and treatment of postmenopausal osteoporosis, and is known to reduce the risk of breast cancer [84]. Earlier in 2018, Forcellini et al reported several novel quinazoline-4-piperidine sulfamide analogs as inhibitors of ENPP1 [85]. Among these, meta-pyridine substituted compound 7c was the most potent compound, with a K i of 58 nM (0.058 µM) [85].…”

Section: Inhibitors Of Enpp1mentioning

confidence: 99%

“…Earlier in 2018, Forcellini et al reported several novel quinazoline-4-piperidine sulfamide analogs as inhibitors of ENPP1 [85]. Among these, meta-pyridine substituted compound 7c was the most potent compound, with a K i of 58 nM (0.058 µM) [85]. More recently, Weston et al reported a new ENPP1 inhibitor, SR-8314, which promotes STING activation [86].…”

Section: Inhibitors Of Enpp1mentioning

confidence: 99%

ENPP1, an Old Enzyme with New Functions, and Small Molecule Inhibitors—A STING in the Tale of ENPP1

Onyedibe

¹

,

Wang

²

,

Sintim

³

2019

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Ectonucleotide pyrophosphatase/phosphodiesterase I (ENPP1) was identified several decades ago as a type II transmembrane glycoprotein with nucleotide pyrophosphatase and phosphodiesterase enzymatic activities, critical for purinergic signaling. Recently, ENPP1 has emerged as a critical phosphodiesterase that degrades the stimulator of interferon genes (STING) ligand, cyclic GMP–AMP (cGAMP). cGAMP or analogs thereof have emerged as potent immunostimulatory agents, which have potential applications in immunotherapy. This emerging role of ENPP1 has placed this “old” enzyme at the frontier of immunotherapy. This review highlights the roles played by ENPP1, the mechanism of cGAMP hydrolysis by ENPP1, and small molecule inhibitors of ENPP1 with potential applications in diverse disease states, including cancer.

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“…25 However, all natural ENPP1 substrates have Km values higher than 20 μM. 19,24 Despite ENPP1 being a highly sought-after target, [26][27][28][29][30][31][32][33][34] developing drug-like ENPP1 inhibitors has proved difficult. Here, we report the development of the most potent ENPP1 inhibitors to date and the co-crystal structure of an exemplary phosphonate inhibitor with ENPP1.…”

Section: Introductionmentioning

confidence: 99%

Structure-Aided Development of Small-Molecule Inhibitors of ENPP1, the Extracellular Phosphodiesterase of the Immunotransmitter cGAMP

Carozza

¹

,

Brown

²

,

Böhnert

³

et al. 2020

Cell Chemical Biology

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Cancer cells initiate an innate immune response by synthesizing and exporting the small molecule immunotransmitter cGAMP, which activates the anti-cancer Stimulator of Interferon Genes (STING) pathway in the host. An extracellular enzyme, ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), hydrolyzes cGAMP and negatively regulates this anti-cancer immune response. Small molecule ENPP1 inhibitors are much needed as tools to study basic biology of extracellular cGAMP and as investigational cancer immunotherapy drugs. Here, we surveyed structure-activity relationships around a series of cell-impermeable and thus extracellular-targeting phosphonate inhibitors of ENPP1. Additionally, we solved the crystal structure of an exemplary phosphonate inhibitor to elucidate the interactions that drive potency. This study yielded several best-in-class compounds with Ki < 2 nM and excellent physicochemical and pharmacokinetic properties. Finally, we demonstrate that an ENPP1 inhibitor delays tumor growth in a breast cancer mouse model. Together, we have developed ENPP1 inhibitors that are excellent tool compounds and potential therapeutics.

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“…We also chose the ethylene linker (compound 15, Ki = 33 nM, previously reported as STF-1084 13 ) because it has been shown previously that for the sulfamides, analogs with shorter linker lengths have less affinity for the cardiac potassium channel hERG, a detrimental off target. 28,32 Co-crystal structure of ENPP1 and compound 15 reveals molecular determinants of potency ENPP1 is a >100 kDa multidomain glycoprotein with three glycosylation chains. It has a catalytic domain, a nuclease-like domain which provides structural support important for catalysis, and two disordered SMB domains.…”

Section: Enpp1 Inhibitors With a Zinc-binding Phosphonate Head Group mentioning

confidence: 99%

Structure-aided development of small molecule inhibitors of ENPP1, the extracellular phosphodiesterase of the immunotransmitter cGAMP

Carozza

¹

,

Brown

²

,

Boehnert

³

et al. 2020

Preprint

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Cancer cells initiate an innate immune response by synthesizing and exporting the small molecule immunotransmitter cGAMP, which activates the anti-cancer Stimulator of Interferon Genes (STING) pathway in the host. An extracellular enzyme, ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), hydrolyzes cGAMP and negatively regulates this anti-cancer immune response. Small molecule ENPP1 inhibitors are much needed as tools to study basic biology of extracellular cGAMP and as investigational cancer immunotherapy drugs. Here, we surveyed structure-activity relationships around a series of cell-impermeable and thus extracellular-targeting phosphonate inhibitors of ENPP1. Additionally, we solved the crystal structure of an exemplary phosphonate inhibitor to elucidate the interactions that drive potency. This study yielded several best-in-class compounds with Ki < 2 nM and excellent physicochemical and pharmacokinetic properties. Finally, we demonstrate that an ENPP1 inhibitor delays tumor growth in a breast cancer mouse model. Together, we have developed ENPP1 inhibitors that are excellent tool compounds and potential therapeutics. J.A.C., M.S., and L.L. designed the study. J.A.C., Y.A.S., and R.E.M. performed enzyme assays and analyzed the data. V.B. performed mouse experiments. J.A.B. and D.F. determined the crystal structure. J.A.C., M.S., and L.L. wrote the paper. All authors discussed the findings and commented on the manuscript. Competing interestsM.S. and L.L. are scientific cofounders of Angarus Therapeutics, which has exclusive licensing rights to patents PCT/US2018/50018 and PCT/US2020/015968. J.A.C., V.B., M.S., and L.L. are inventors on patents PCT/US2018/50018 and PCT/US2020/015968.

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Synthesis and biological evaluation of novel quinazoline-4-piperidinesulfamide derivatives as inhibitors of NPP1

Cited by 24 publications

References 40 publications

ENPP1, an Old Enzyme with New Functions, and Small Molecule Inhibitors—A STING in the Tale of ENPP1

ENPP1, an Old Enzyme with New Functions, and Small Molecule Inhibitors—A STING in the Tale of ENPP1

Structure-Aided Development of Small-Molecule Inhibitors of ENPP1, the Extracellular Phosphodiesterase of the Immunotransmitter cGAMP

Structure-aided development of small molecule inhibitors of ENPP1, the extracellular phosphodiesterase of the immunotransmitter cGAMP

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