Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

Wan, Honghe; Schroeder, G.; Hart, Andrew; Inghrim, Jennifer; Grebinski, James; Tokarski, John S.; Lorenzi, Matthew V.; You, Dan; McDevitt, Theresa M.; Penhallow, Becky; Vuppugalla, Ragini; Zhang, Yueping; Gu, Xiaomei; Iyer, Ramaswamy A.; Lombardo, Louis J.; Trainor, George L.; Ruepp, Stefan; Lippy, Jonathan; Blat, Yuval; Sack, John S.; Khan, Javed; Stefanski, Kevin; Sleczka, Bogdan; Mathur, Arvind; Sun, Jung‐Hui; Wong, Michael K.; Wu, Dauh‐Rurng; Gupta, Anuradha; Arunachalam, Piramanayagam; Pragalathan, Bala; Narayanan, Sankara; K.C., Nanjundaswamy; Kuppusamy, Prakasam; Purandare, Ashok V.

doi:10.1021/acsmedchemlett.5b00226

Cited by 35 publications

(17 citation statements)

References 21 publications

(44 reference statements)

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“…Molecular modeling suggested that a trajectory from a sp 2 center would more effectively traverse the opening between the P-loop and extended hinge region toward solvent. Appending the 2-methoxyethyl side chain to the scaffold through a sp 2 hybridized linker (13,14) maintained planarity with the azaindole core and further improved potency against JAK2 while preserving JAK family selectivity. Despite the improved selectivity, these compounds (12,13,14) were less potent than the methyl analogue (8).…”

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confidence: 99%

“…Appending the 2-methoxyethyl side chain to the scaffold through a sp 2 hybridized linker (13,14) maintained planarity with the azaindole core and further improved potency against JAK2 while preserving JAK family selectivity. Despite the improved selectivity, these compounds (12,13,14) were less potent than the methyl analogue (8). An amide isostere, thiazole (15), improved potency and cellular activity, while retaining comparable levels of selectivity to the methoxyalkyl analogues.…”

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confidence: 99%

“…Access to scaffold 19 was available via a similar synthetic sequence to that described for the C4-NHMe analogues. Deprotection provided the free amine 20, which could undergo reductive amination (12), chloroformate or isocyanate coupling (13,14), or Buchwald− Hartwig coupling (15).…”

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confidence: 99%

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Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors

Hart

Schroeder

Wan

et al. 2015

ACS Med. Chem. Lett.

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Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

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confidence: 99%

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confidence: 99%

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Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors

Hart

Schroeder

Wan

et al. 2015

ACS Med. Chem. Lett.

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“…29 The incubation mixtures contained the following components: 1.1 nM JAK1/2/3, 1.5 mM peptide substrate (5-FAM-KKKKEEIYFFFG-OH for JAK2) and 30 mM ATP. Aer the incubation for 180 min, the reaction mixture was analyzed on a Caliper LabChip 3000 (Caliper LifeSciences, Hopinkton, MA, USA) by electrophoretic separation of the uorescent substrate and phosphorylated product.…”

Section: In Vitro Jak Inhibition Assaysmentioning

confidence: 99%

Integration of pharmacophore mapping and molecular docking in sequential virtual screening: towards the discovery of novel JAK2 inhibitors

et al. 2017

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An integrated virtual screening protocol by combining molecular docking and pharmacophore mapping was established to identify novel inhibitors of JAK2 from a commercial compound database. Twelve novel and structurally diverse hits were selected and subjected to in vitro biological tests, and three compounds (A5, A6 and A9) with remarkable JAK2 inhibitory activity were identified. Then, the obtained structures were further used as the template for a subsequent similarity search, leading to the identification of another two promising compounds (B2 and B4). Selectivity profiles of JAK subtype and in vitro anti-cancer activity of the promising compounds were studied, revealing the promising compound B2 was of interest for further study because of its JAK2 selective profile, novelty of skeleton and significantly anti-proliferative effect against cancer cells. Finally, binding patterns of the compounds A5 and B2 were explored to provide a deeper insight for further structural optimization.

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“…Some pyrazole‐based drugs are depicted in Figure . Pyrazole derivatives show anticancer activity due to their inhibition of various targets such as EGFR , IGF‐1R , tubulin , B‐raf , mTOR , HDAC , ALK , topoisomerase II , JAK2 , ROS 1 , among others. Hence, incorporation of the pyrazole moiety is an important synthetic strategy in rational drug development process.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Some Novel Heterocycles Bearing Pyrazole Moiety as Potential Anticancer Agents

Abdelgawad

Ismail

Hekal

et al. 2019

Journal of Heterocyclic Chem

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1,3‐Diphenylpyrazole‐4‐carboxylaldehyde and o‐hydroxyacetophenone were exploited as starting materials for the synthesis of novel substituted chalconated pyrazole derivative. The proclivity of this compound towards carbon and nitrogen nucleophiles such as malononitrile, diethyl malonate, ethyl cyanoacetate, ethyl acetoacetate, semicarbazide, thiosemicarbazide, and hydroxylamine has been investigated. The structures of all synthesized compounds were ascertained by analytical and spectral data. The antitumor activity of the target synthesized compounds was tested against a panel of two human tumor cell lines, namely, hepatocellular carcinoma (liver) HepG2 and mammary gland breast MCF‐7.

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Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

Cited by 35 publications

References 21 publications

Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors

Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors

Integration of pharmacophore mapping and molecular docking in sequential virtual screening: towards the discovery of novel JAK2 inhibitors

Design, Synthesis, and Evaluation of Some Novel Heterocycles Bearing Pyrazole Moiety as Potential Anticancer Agents

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