Selective and reversible modification of kinase cysteines with chlorofluoroacetamides

Naoya Shindo, Hirokazu Fuchida, Mami Sato, Kosuke Watari, Tomohiro Shibata, Keiko Kuwata, Chizuru Miura, Kei Okamoto, Yuji Hatsuyama, Keisuke Tokunaga, Seiichi Sakamoto, Satoshi Morimoto, Yoshito Abe, Mitsunori Shiroishi, Jose M M Caaveiro, Tadashi Ueda, Tomonori Tamura, Naoya Matsunaga, Takaharu Nakao, Satoru KoyanagiShigehiro Ohdo, Yasuchika Yamaguchi, Itaru Hamachi, Mayumi Ono, Akio Ojida

研究成果: ジャーナルへの寄稿記事

7 引用 (Scopus)

抄録

Irreversible inhibition of disease-associated proteins with small molecules is a powerful approach for achieving increased and sustained pharmacological potency. Here, we introduce α-chlorofluoroacetamide (CFA) as a novel warhead of targeted covalent inhibitor (TCI). Despite weak intrinsic reactivity, CFA-appended quinazoline showed high reactivity toward Cys797 of epidermal growth factor receptor (EGFR). In cells, CFA-quinazoline showed higher target specificity for EGFR than the corresponding Michael acceptors in a wide concentration range (0.1-10 μM). The cysteine adduct of the CFA derivative was susceptible to hydrolysis and reversibly yielded intact thiol but was stable in solvent-sequestered ATP-binding pocket of EGFR. This environment-dependent hydrolysis can potentially reduce off-target protein modification by CFA-based drugs. Oral administration of CFA quinazoline NS-062 significantly suppressed tumor growth in a mouse xenograft model. Further, CFA-appended pyrazolopyrimidine irreversibly inhibited Bruton's tyrosine kinase with higher target specificity. These results demonstrate the utility of CFA as a new class warheads for TCI.

元の言語英語
ジャーナルNature Chemical Biology
DOI
出版物ステータス印刷前のE-pub - 1 14 2019

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Quinazolines
Epidermal Growth Factor Receptor
Cysteine
Phosphotransferases
Hydrolysis
Sulfhydryl Compounds
Heterografts
Oral Administration
Proteins
Adenosine Triphosphate
Pharmacology
Growth
Pharmaceutical Preparations
Neoplasms

これを引用

Selective and reversible modification of kinase cysteines with chlorofluoroacetamides. / Shindo, Naoya; Fuchida, Hirokazu; Sato, Mami; Watari, Kosuke; Shibata, Tomohiro; Kuwata, Keiko; Miura, Chizuru; Okamoto, Kei; Hatsuyama, Yuji; Tokunaga, Keisuke; Sakamoto, Seiichi; Morimoto, Satoshi; Abe, Yoshito; Shiroishi, Mitsunori; Caaveiro, Jose M M; Ueda, Tadashi; Tamura, Tomonori; Matsunaga, Naoya; Nakao, Takaharu; Koyanagi, Satoru; Ohdo, Shigehiro; Yamaguchi, Yasuchika; Hamachi, Itaru; Ono, Mayumi; Ojida, Akio.

:: Nature Chemical Biology, 14.01.2019.

研究成果: ジャーナルへの寄稿記事

Shindo, N, Fuchida, H, Sato, M, Watari, K, Shibata, T, Kuwata, K, Miura, C, Okamoto, K, Hatsuyama, Y, Tokunaga, K, Sakamoto, S, Morimoto, S, Abe, Y, Shiroishi, M, Caaveiro, JMM, Ueda, T, Tamura, T, Matsunaga, N, Nakao, T, Koyanagi, S, Ohdo, S, Yamaguchi, Y, Hamachi, I, Ono, M & Ojida, A 2019, 'Selective and reversible modification of kinase cysteines with chlorofluoroacetamides', Nature Chemical Biology. https://doi.org/10.1038/s41589-018-0204-3
Shindo, Naoya ; Fuchida, Hirokazu ; Sato, Mami ; Watari, Kosuke ; Shibata, Tomohiro ; Kuwata, Keiko ; Miura, Chizuru ; Okamoto, Kei ; Hatsuyama, Yuji ; Tokunaga, Keisuke ; Sakamoto, Seiichi ; Morimoto, Satoshi ; Abe, Yoshito ; Shiroishi, Mitsunori ; Caaveiro, Jose M M ; Ueda, Tadashi ; Tamura, Tomonori ; Matsunaga, Naoya ; Nakao, Takaharu ; Koyanagi, Satoru ; Ohdo, Shigehiro ; Yamaguchi, Yasuchika ; Hamachi, Itaru ; Ono, Mayumi ; Ojida, Akio. / Selective and reversible modification of kinase cysteines with chlorofluoroacetamides. :: Nature Chemical Biology. 2019.
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abstract = "Irreversible inhibition of disease-associated proteins with small molecules is a powerful approach for achieving increased and sustained pharmacological potency. Here, we introduce α-chlorofluoroacetamide (CFA) as a novel warhead of targeted covalent inhibitor (TCI). Despite weak intrinsic reactivity, CFA-appended quinazoline showed high reactivity toward Cys797 of epidermal growth factor receptor (EGFR). In cells, CFA-quinazoline showed higher target specificity for EGFR than the corresponding Michael acceptors in a wide concentration range (0.1-10 μM). The cysteine adduct of the CFA derivative was susceptible to hydrolysis and reversibly yielded intact thiol but was stable in solvent-sequestered ATP-binding pocket of EGFR. This environment-dependent hydrolysis can potentially reduce off-target protein modification by CFA-based drugs. Oral administration of CFA quinazoline NS-062 significantly suppressed tumor growth in a mouse xenograft model. Further, CFA-appended pyrazolopyrimidine irreversibly inhibited Bruton's tyrosine kinase with higher target specificity. These results demonstrate the utility of CFA as a new class warheads for TCI.",
author = "Naoya Shindo and Hirokazu Fuchida and Mami Sato and Kosuke Watari and Tomohiro Shibata and Keiko Kuwata and Chizuru Miura and Kei Okamoto and Yuji Hatsuyama and Keisuke Tokunaga and Seiichi Sakamoto and Satoshi Morimoto and Yoshito Abe and Mitsunori Shiroishi and Caaveiro, {Jose M M} and Tadashi Ueda and Tomonori Tamura and Naoya Matsunaga and Takaharu Nakao and Satoru Koyanagi and Shigehiro Ohdo and Yasuchika Yamaguchi and Itaru Hamachi and Mayumi Ono and Akio Ojida",
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AU - Shindo, Naoya

AU - Fuchida, Hirokazu

AU - Sato, Mami

AU - Watari, Kosuke

AU - Shibata, Tomohiro

AU - Kuwata, Keiko

AU - Miura, Chizuru

AU - Okamoto, Kei

AU - Hatsuyama, Yuji

AU - Tokunaga, Keisuke

AU - Sakamoto, Seiichi

AU - Morimoto, Satoshi

AU - Abe, Yoshito

AU - Shiroishi, Mitsunori

AU - Caaveiro, Jose M M

AU - Ueda, Tadashi

AU - Tamura, Tomonori

AU - Matsunaga, Naoya

AU - Nakao, Takaharu

AU - Koyanagi, Satoru

AU - Ohdo, Shigehiro

AU - Yamaguchi, Yasuchika

AU - Hamachi, Itaru

AU - Ono, Mayumi

AU - Ojida, Akio

PY - 2019/1/14

Y1 - 2019/1/14

N2 - Irreversible inhibition of disease-associated proteins with small molecules is a powerful approach for achieving increased and sustained pharmacological potency. Here, we introduce α-chlorofluoroacetamide (CFA) as a novel warhead of targeted covalent inhibitor (TCI). Despite weak intrinsic reactivity, CFA-appended quinazoline showed high reactivity toward Cys797 of epidermal growth factor receptor (EGFR). In cells, CFA-quinazoline showed higher target specificity for EGFR than the corresponding Michael acceptors in a wide concentration range (0.1-10 μM). The cysteine adduct of the CFA derivative was susceptible to hydrolysis and reversibly yielded intact thiol but was stable in solvent-sequestered ATP-binding pocket of EGFR. This environment-dependent hydrolysis can potentially reduce off-target protein modification by CFA-based drugs. Oral administration of CFA quinazoline NS-062 significantly suppressed tumor growth in a mouse xenograft model. Further, CFA-appended pyrazolopyrimidine irreversibly inhibited Bruton's tyrosine kinase with higher target specificity. These results demonstrate the utility of CFA as a new class warheads for TCI.

AB - Irreversible inhibition of disease-associated proteins with small molecules is a powerful approach for achieving increased and sustained pharmacological potency. Here, we introduce α-chlorofluoroacetamide (CFA) as a novel warhead of targeted covalent inhibitor (TCI). Despite weak intrinsic reactivity, CFA-appended quinazoline showed high reactivity toward Cys797 of epidermal growth factor receptor (EGFR). In cells, CFA-quinazoline showed higher target specificity for EGFR than the corresponding Michael acceptors in a wide concentration range (0.1-10 μM). The cysteine adduct of the CFA derivative was susceptible to hydrolysis and reversibly yielded intact thiol but was stable in solvent-sequestered ATP-binding pocket of EGFR. This environment-dependent hydrolysis can potentially reduce off-target protein modification by CFA-based drugs. Oral administration of CFA quinazoline NS-062 significantly suppressed tumor growth in a mouse xenograft model. Further, CFA-appended pyrazolopyrimidine irreversibly inhibited Bruton's tyrosine kinase with higher target specificity. These results demonstrate the utility of CFA as a new class warheads for TCI.

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