Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors

Hee Jin Jeong; Hye Lim Lee; Sung Joon Kim; Jeong Hyun Jeong; Su Hyun Ji; Han Byeol Kim; Miso Kang; Hwan Won Chung; Chan Sun Park; Hyunah Choo; Hyo Jae Yoon; Nam Jung Kim; Duck Hyung Lee; Sang Hee Lee; Seo Jung Han

doi:10.1080/14756366.2022.2119566

Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors

Hee Jin Jeong, Hye Lim Lee, Sung Joon Kim, Jeong Hyun Jeong, Su Hyun Ji, Han Byeol Kim, Miso Kang, Hwan Won Chung, Chan Sun Park, Hyunah Choo, Hyo Jae Yoon, Nam Jung Kim, Duck Hyung Lee, Sang Hee Lee, Seo Jung Han

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of Interferon Genes (STING) pathway, we designed and synthesised pyrrolopyrimidine and pyrrolopyridine derivatives and performed structure-activity relationship (SAR) study. We found 18p possessed high potency (IC₅₀ = 25.0 nM) against ENPP1, and activated STING pathway in a concentration dependent manner. Also, in response to STING pathway activation, cytokines such as IFN-β and IP-10 were induced by 18p in a concentration dependent manner. Finally, we discovered that 18p causes inhibition of tumour growth in 4T1 syngeneic mouse model. This study provides new insight into the designing of novel ENPP1 inhibitors and warrants further development of small molecule immune modulators for cancer immunotherapy.

Original language	English
Pages (from-to)	2434-2451
Number of pages	18
Journal	Journal of Enzyme Inhibition and Medicinal Chemistry
Volume	37
Issue number	1
DOIs	https://doi.org/10.1080/14756366.2022.2119566
Publication status	Published - 2022

Bibliographical note

Funding Information:
This study was supported by KIST Institutional Program [2E31624, 2E31690, 2V09235, 2E31629, 2E3162D, 2E31512 and 2E31524], the National Research Foundation of Korea (NRF) [2021R1C1C1005134], the Technology Development Program to Solve Climate Change of the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT [NRF-2020M1A2A2079798]. This research was also supported by the National Research Council of Science & Technology (NST) granted by the Korea government(MSIT) [No. CPS21061-100]. Additionally, this research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare [HN22C0063000022, Republic of Korea].

Publisher Copyright:
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Keywords

ENPP1
STING
cancer immunotherapy
innate immunity

ASJC Scopus subject areas

Pharmacology
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1080/14756366.2022.2119566

Cite this

Jeong, H. J., Lee, H. L., Kim, S. J., Jeong, J. H., Ji, S. H., Kim, H. B., Kang, M., Chung, H. W., Park, C. S., Choo, H., Yoon, H. J., Kim, N. J., Lee, D. H., Lee, S. H., & Han, S. J. (2022). Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 37(1), 2434-2451. https://doi.org/10.1080/14756366.2022.2119566

Jeong, HJ, Lee, HL, Kim, SJ, Jeong, JH, Ji, SH, Kim, HB, Kang, M, Chung, HW, Park, CS, Choo, H, Yoon, HJ, Kim, NJ, Lee, DH, Lee, SH & Han, SJ 2022, 'Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors', Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 37, no. 1, pp. 2434-2451. https://doi.org/10.1080/14756366.2022.2119566

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title = "Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors",

abstract = "In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of Interferon Genes (STING) pathway, we designed and synthesised pyrrolopyrimidine and pyrrolopyridine derivatives and performed structure-activity relationship (SAR) study. We found 18p possessed high potency (IC50 = 25.0 nM) against ENPP1, and activated STING pathway in a concentration dependent manner. Also, in response to STING pathway activation, cytokines such as IFN-β and IP-10 were induced by 18p in a concentration dependent manner. Finally, we discovered that 18p causes inhibition of tumour growth in 4T1 syngeneic mouse model. This study provides new insight into the designing of novel ENPP1 inhibitors and warrants further development of small molecule immune modulators for cancer immunotherapy.",

keywords = "ENPP1, STING, cancer immunotherapy, innate immunity",

author = "Jeong, \{Hee Jin\} and Lee, \{Hye Lim\} and Kim, \{Sung Joon\} and Jeong, \{Jeong Hyun\} and Ji, \{Su Hyun\} and Kim, \{Han Byeol\} and Miso Kang and Chung, \{Hwan Won\} and Park, \{Chan Sun\} and Hyunah Choo and Yoon, \{Hyo Jae\} and Kim, \{Nam Jung\} and Lee, \{Duck Hyung\} and Lee, \{Sang Hee\} and Han, \{Seo Jung\}",

note = "Funding Information: This study was supported by KIST Institutional Program [2E31624, 2E31690, 2V09235, 2E31629, 2E3162D, 2E31512 and 2E31524], the National Research Foundation of Korea (NRF) [2021R1C1C1005134], the Technology Development Program to Solve Climate Change of the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT [NRF-2020M1A2A2079798]. This research was also supported by the National Research Council of Science \& Technology (NST) granted by the Korea government(MSIT) [No. CPS21061-100]. Additionally, this research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare [HN22C0063000022, Republic of Korea]. Publisher Copyright: {\textcopyright} 2022 The Author(s). Published by Informa UK Limited, trading as Taylor \& Francis Group.",

year = "2022",

doi = "10.1080/14756366.2022.2119566",

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T1 - Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors

AU - Jeong, Hee Jin

AU - Lee, Hye Lim

AU - Kim, Sung Joon

AU - Jeong, Jeong Hyun

AU - Ji, Su Hyun

AU - Kim, Han Byeol

AU - Kang, Miso

AU - Chung, Hwan Won

AU - Park, Chan Sun

AU - Choo, Hyunah

AU - Yoon, Hyo Jae

AU - Kim, Nam Jung

AU - Lee, Duck Hyung

AU - Lee, Sang Hee

AU - Han, Seo Jung

N1 - Funding Information: This study was supported by KIST Institutional Program [2E31624, 2E31690, 2V09235, 2E31629, 2E3162D, 2E31512 and 2E31524], the National Research Foundation of Korea (NRF) [2021R1C1C1005134], the Technology Development Program to Solve Climate Change of the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT [NRF-2020M1A2A2079798]. This research was also supported by the National Research Council of Science & Technology (NST) granted by the Korea government(MSIT) [No. CPS21061-100]. Additionally, this research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare [HN22C0063000022, Republic of Korea]. Publisher Copyright: © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

PY - 2022

Y1 - 2022

N2 - In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of Interferon Genes (STING) pathway, we designed and synthesised pyrrolopyrimidine and pyrrolopyridine derivatives and performed structure-activity relationship (SAR) study. We found 18p possessed high potency (IC50 = 25.0 nM) against ENPP1, and activated STING pathway in a concentration dependent manner. Also, in response to STING pathway activation, cytokines such as IFN-β and IP-10 were induced by 18p in a concentration dependent manner. Finally, we discovered that 18p causes inhibition of tumour growth in 4T1 syngeneic mouse model. This study provides new insight into the designing of novel ENPP1 inhibitors and warrants further development of small molecule immune modulators for cancer immunotherapy.

AB - In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of Interferon Genes (STING) pathway, we designed and synthesised pyrrolopyrimidine and pyrrolopyridine derivatives and performed structure-activity relationship (SAR) study. We found 18p possessed high potency (IC50 = 25.0 nM) against ENPP1, and activated STING pathway in a concentration dependent manner. Also, in response to STING pathway activation, cytokines such as IFN-β and IP-10 were induced by 18p in a concentration dependent manner. Finally, we discovered that 18p causes inhibition of tumour growth in 4T1 syngeneic mouse model. This study provides new insight into the designing of novel ENPP1 inhibitors and warrants further development of small molecule immune modulators for cancer immunotherapy.

KW - ENPP1

KW - STING

KW - cancer immunotherapy

KW - innate immunity

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U2 - 10.1080/14756366.2022.2119566

DO - 10.1080/14756366.2022.2119566

M3 - Article

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AN - SCOPUS:85137311073

SN - 1475-6366

VL - 37

SP - 2434

EP - 2451

JO - Journal of Enzyme Inhibition and Medicinal Chemistry

JF - Journal of Enzyme Inhibition and Medicinal Chemistry

IS - 1

ER -

Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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