Design, synthesis and structure-activity relationship studies of pyrido[2,3-d]pyrimidin-7-ones as potent Janus Kinase 3 (JAK3) covalent inhibitors

Su, Wenhong; Chen, Zhiwen; He, Rong; Liu, Chaoyi; Li, Rui; Gao, Mingshan; Zheng, Mingyue; Tu, Zhengchao; Zhang, Zhang; Xu, Tianfeng

doi:10.1016/j.bmcl.2022.128680

Cited by 6 publications

(6 citation statements)

References 24 publications

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“…Previous studies on developing covalently bound JAK3 inhibitors have revealed that residues Lys855, Leu905, Pro906, Cys909, Asp912, and Arg953 are involved in ligand binding [ 19 , 20 , 21 , 22 , 23 , 26 , 28 ]. From the key residues in the multiple sequence alignment ( Figure S1 , Table 1 ), one can conclude that the most unique residue for selective JAK3 binding is cysteine 909.…”

Section: Resultsmentioning

confidence: 99%

“…Due to the highly conserved structural features of the ATP binding pocket, it has been challenging to achieve high selectivity among the JAK family. Many recent developments of JAK3 inhibitors have been focused on a JAK3 unique cysteine residue (CYS909) by forming a covalent bond with JAK3 inhibitors [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. The idea of developing an inhibitor that can covalently bind to cysteine 909 was from other covalent drugs such as afatinib, osimertinib, and ibrutinib ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

“…Three drugs in Figure 2 shared a common α,β-unsaturated amide moiety to allow the Michael addition to the target protein via covalent binding. A number of JAK3 covalently bound inhibitors have been reported and some have been studied under various stages of clinical trials [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Docking and Selectivity Studies of Covalently Bound Janus Kinase 3 Inhibitors

Zhong

Almahmoud

2023

IJMS

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The Janus kinases (JAKs) are a family of non-receptor cytosolic protein kinases critical for immune signaling. Many covalently bound ligands of JAK3 inhibitors have been reported. To help design selective JAK inhibitors, in this paper, we used five model proteins to study the subtype selectivity of and the mutational effects on inhibitor binding. We also compared the Covalent Dock programs from the Schrodinger software suite and the MOE software suite to determine which method to use for the drug design of covalent inhibitors. Our results showed that the docking affinity from 4Z16 (JAK3 wild-type model), 4E4N (JAK1), 4D1S (JAK2), and 7UYT (TYK2) from the Schrödinger software suite agreed well with the experimentally derived binding free energies with small predicted mean errors. However, the data from the mutant 5TTV model using the Schrödinger software suite yielded relatively large mean errors, whereas the MOE Covalent Dock program gave small mean errors in both the wild-type and mutant models for our model proteins. The docking data revealed that Leu905 of JAK3 and the hydrophobic residue at the same position in different subtypes (Leu959 of JAK1, Leu932 of JAK2, and Val981 of TYK2) is important for ligand binding to the JAK proteins. Arg911 and Asp912 of JAK3, Asp939 of JAK2, and Asp988 of TYK2 can be used for selective binding over JAK1, which contains Lys965 and Glu966 at the respective positions. Asp1021, Asp1039, and Asp1042 can be utilized for JAK1-selective ligand design, whereas Arg901 and Val981 may help guide TYK2-selective molecule design.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Docking and Selectivity Studies of Covalently Bound Janus Kinase 3 Inhibitors

Zhong

Almahmoud

2023

IJMS

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“…Dysregulation of the JAK/STAT pathway has been implicated in the development of various autoimmune disorders and cancers, highlighting the significance of JAKs as desirable therapeutic targets for the prevention and treatment of cancer (Tzeng et al, 2021). Su et al, in their recent medicinal chemistry endeavour, designed and reported a new class of pyrido[2,3‐ d ]pyrimidin‐7‐ones as potential covalent inhibitors targeting JAK3 (Su et al, 2022). The initial evaluation revealed that compound 33 (Figure 7) exhibited high potency and selectivity as a JAK3 covalent inhibitor, with an IC 50 value of 2.0 nM.…”

Section: Covalent Inhibitors Of Protein Kinasesmentioning

confidence: 99%

Covalent inhibitors: An ambitious approach for the discovery of newer oncotherapeutics

Cheke,

Kharkar

2023

Drug Development Research

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Covalent inhibitors have been used to treat several diseases for over a century. However, strategic approaches for the rational design of covalent drugs have taken a definitive shape in recent times. Since the first appearance of covalent inhibitors in the late 18th century, the field has grown tremendously and around 30% of marketed drugs are covalent inhibitors especially, for oncology indications. However, the off‐target toxicity and safety concerns can be significant issues related to the covalent drugs. Covalent kinase inhibitor (CKI) targeted oncotherapeutics has advanced dramatically over the last two decades since the discovery of afatinib (Gilotrif®), an EGFR inhibitor. Since then, US FDA has approved 10 CKIs for diverse cancer targets. The present review broadly summarizes the ongoing development in the discovery of newer CKIs from 2016 till the end of 2022. We believe that these efforts will assist the modern medicinal chemist actively working in the field of CKI discovery for varied indications.

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“…In the non-covalent JAK2 JH2 ligands developed in our lab, − selectivity is promoted through a combination of a carboxylate that interacts with Thr555 and Arg715 and a terminal aryl pharmacophore that interacts with Arg715 and Trp718. , Acquiring selectivity is challenging for kinase inhibitors, owing to the abundance of kinases and the sequence conservation in their ATP-binding sites. Thus, the use of targeted covalent inhibitors (TCIs) has been receiving increased attention as an alternative approach to enable high kinase selectivity. − The Janus kinases are no exception, and covalent inhibitors acting on the JAK3 JH1 domain have been developed. − In addition, one compound, xanthatin, has been shown to bind covalently to Cys243 of the FERM domain of JAK2 …”

mentioning

confidence: 99%

Covalent Modification of the JH2 Domain of Janus Kinase 2

Henry

Liosi

Ippolito

et al. 2022

ACS Med. Chem. Lett.

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Probe molecules that covalently modify the JAK2 pseudokinase domain (JH2) are reported. Selective targeting of JH2 domains over the kinase (JH1) domains is a necessary feature for ligands intended to evaluate JH2 domains as therapeutic targets. The JH2 domains of three Janus kinases (JAK1, JAK2, and TYK2) possess a cysteine residue in the catalytic loop that does not occur in their JH1 domains. Starting from a non-selective kinase binding molecule, computer-aided design directed attachment of substituents terminating in acrylamide warheads to modify Cys675 of JAK2 JH2. Successful covalent attachment was demonstrated first through observation of enhanced binding with increasing incubation time in fluorescence polarization experiments. Covalent binding also increased selectivity to as much as ca. 30fold for binding the JAK2 JH2 domain over the JH1 domain after a 20-h incubation. Covalency was confirmed through HPLC electrospray quadrupole time-of-flight HRMS experiments, which revealed the expected mass shifts.

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Design, synthesis and structure-activity relationship studies of pyrido[2,3-d]pyrimidin-7-ones as potent Janus Kinase 3 (JAK3) covalent inhibitors

Cited by 6 publications

References 24 publications

Docking and Selectivity Studies of Covalently Bound Janus Kinase 3 Inhibitors

Docking and Selectivity Studies of Covalently Bound Janus Kinase 3 Inhibitors

Covalent inhibitors: An ambitious approach for the discovery of newer oncotherapeutics

Covalent Modification of the JH2 Domain of Janus Kinase 2

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