Discovery of DS-5272 as a promising candidate: A potent and orally active p53–MDM2 interaction inhibitor

Miyazaki, Masaki; Uoto, Kouichi; Sugimoto, Yuuichi; Naito, Hiroyuki; Yoshida, Keisuke; Okayama, Tooru; Kawato, Haruko C.; Miyazaki, Masaya; Kitagawa, Mayumi; Seki, Takahiko; Fukutake, Setsuko; Aonuma, Masashi; Soga, Tsunehiko

doi:10.1016/j.bmc.2015.03.069

Cited by 35 publications

(25 citation statements)

References 22 publications

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“…[39][40][41] DS-5272, derived from a candidate MDM2 inhibitor by chemical modifications to improve its potency and physicochemical property, is a highly selective and potent MDM2 inhibitor. 42 Although we cannot state that DS-5272 works entirely in a p53-dependent manner, especially since MDM2 has functions other than antagonizing p53, its use alone or in combination with a TKI increased p53, NOXA, and BAX suggesting that it functions, at least in part, through increasing the p53 signaling.…”

Section: Discussionmentioning

confidence: 90%

Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model

Carter

Mak

et al. 2019

Haematologica

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Section: Discussionmentioning

confidence: 90%

Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model

Carter

Mak

et al. 2019

Haematologica

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“…Inspired by this mode of reactivity, and deducing that pyridinylmethanamine can be viewed simply as the core unit of a pyridoxamine, we surmised that chiral aldehyde catalysis might be effective for the asymmetric α-functionalization of pyridinylmethanamines. The chiral pyridinylmethanamine unit is found frequently in biologically active compounds 47 – 49 , chiral ligands 50 – 53 and natural products 54 – 58 , so the preparation of optically active pyridinylmethanamine derivatives is highly valuable work.…”

Section: Resultsmentioning

confidence: 99%

Diastereodivergent chiral aldehyde catalysis for asymmetric 1,6-conjugated addition and Mannich reactions

Wen

Luo

et al. 2020

Nat Commun

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Chiral aldehyde catalysis is a burgeoning strategy for the catalytic asymmetric α-functionalization of aminomethyl compounds. However, the reaction types are limited and to date include no examples of stereodivergent catalysis. In this work, we disclose two chiral aldehyde-catalysed diastereodivergent reactions: a 1,6-conjugate addition of amino acids to para-quinone methides and a bio-inspired Mannich reaction of pyridinylmethanamines and imines. Both the syn- and anti-products of these two reactions can be obtained in moderate to high yields, diastereo- and enantioselectivities. Four potential reaction models produced by DFT calculations are proposed to explain the observed stereoselective control. Our work shows that chiral aldehyde catalysis based on a reversible imine formation principle is applicable for the α-functionalization of both amino acids and aryl methylamines, and holds potential to promote a range of asymmetric transformations diastereoselectively.

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“…The MDM2 inhibitor, (6R)‐7‐[(4R)‐1‐{[(5R,6S)‐5‐(4‐chloro‐3‐fluorophenyl)‐6‐ (6‐chloropyridin‐3‐yl)‐3‐isopropyl‐6‐methyl‐5,6‐ dihydroimidazo[2,1‐b][1,3]thiazol‐2‐yl]carbonyl}‐4‐fluoro‐L‐ prolyl]‐6‐ethyl‐4,7‐diazaspiro[2.5]octane (DS‐5272), was provided by Daiichi Sankyou Co. Ltd. (Tokyo, Japan). This inhibitor was developed by Miyazaki et al and its chemical structure was shown previously . Each treatment group had been subdivided to receive either 10 mg/kg DS‐5272 or vehicle intraperitoneally 24 hours before and just after the cisplatin injection.…”

Section: Methodsmentioning

confidence: 99%

“…This inhibitor was developed by Miyazaki et al and its chemical structure was shown previously. 15 Each treatment group had been subdivided to receive either 10 mg/kg DS-5272 or vehicle intraperitoneally 24 hours before and just after the cisplatin injection.…”

Section: Animal Studiesmentioning

confidence: 99%

MDM2 inhibitor ameliorates cisplatin‐induced nephropathy via NFκΒ signal inhibition

Fujikura

Yasuda

Iwakura

et al. 2018

Pharmacology Res & Perspec

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Cisplatin is a platinum‐containing chemotherapeutic drug, which is widely used and highly effective. While effective against tumors, its use is limited by severe side effects such as nephrotoxicity and bone marrow suppression. Murine double minute 2 (MDM2) is the E3 ubiquitin ligase of the tumor suppressor gene, p53, and inhibition of MDM2 can suppress tumor cell growth. However, independent of p53, MDM2 acts as a co‐transcription factor for nuclear factor‐κB (NFκB), whose signaling can be involved in cisplatin‐induced tubular injury. We therefore examined the effects of MDM2 inhibitor on cisplatin cytotoxicity. In order to induce acute kidney injury and to investigate MDM2 inhibitory effects, we injected cisplatin into rats with or without the MDM2 inhibitor, DS‐5272, and analyzed kidney physiology/histology and NFκB signaling. Serum creatinine was significantly lower in the DS‐5272 group than in the vehicle group on day 3 (0.55 ± 0.069 vs 0.70 ± 0.072 mg/dL, P < 0.05). DS‐5272 also significantly decreased kidney injury molecule‐1 (KIM‐1) expression, improved tubular injury, and decreased apoptotic cells. Western blotting showed that cisplatin increased NFκB phosphorylation in kidneys, which was significantly suppressed by DS‐5272. In vitro, we treated HEK 293 cells with cisplatin, in the absence or presence of DS‐5272, and examined cytotoxicity and NFκB transcriptional activity. DS‐5272 co‐treatment reduced both cisplatin‐induced cell death and NFκB transcriptional activity. Collectively, these findings suggest that DS‐5272 can ameliorate cisplatin nephrotoxicity via NFκB signal inhibition.

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Discovery of DS-5272 as a promising candidate: A potent and orally active p53–MDM2 interaction inhibitor

Cited by 35 publications

References 22 publications

Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model

Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model

Diastereodivergent chiral aldehyde catalysis for asymmetric 1,6-conjugated addition and Mannich reactions

MDM2 inhibitor ameliorates cisplatin‐induced nephropathy via NFκΒ signal inhibition

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