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Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors.

Burger MT, Han W, Lan J, Nishiguchi G, Bellamacina C, Lindval M, Atallah G, Ding Y, Mathur M, McBride C, Beans EL, Muller K, Tamez V, Zhang Y, Huh K, Feucht P, Zavorotinskaya T, Dai Y, Holash J, Castillo J, Langowski J, Wang Y, Chen MY, Garcia PD
ACS Med Chem Lett 4 1193-7 (2013)
Related entries: 4n6z, 4n70

Cited: 18 times
EuropePMC logo PMID: 24900629

Abstract

Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts toward this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000-fold to yield compounds with pan PIM K is < 10 pM, nanomolar cellular potency, and in vivo activity in an acute myeloid leukemia Pim-dependent tumor model is described.

Reviews citing this publication (5)

  1. Targeting the Pim kinases in multiple myeloma. Keane NA, Reidy M, Natoni A, Raab MS, O'Dwyer M. Blood Cancer J 5 e325 (2015)
  2. Pharmacology of Modulators of Alternative Splicing. Bates DO, Morris JC, Oltean S, Donaldson LF. Pharmacol. Rev. 69 63-79 (2017)
  3. Targeting Pim kinases for cancer treatment: opportunities and challenges. Le BT, Kumarasiri M, Adams JR, Yu M, Milne R, Sykes MJ, Wang S. Future Med Chem 7 35-53 (2015)
  4. Five Years of the KNIME Vernalis Cheminformatics Community Contribution. Roughley SD. Curr Med Chem 27 6495-6522 (2020)
  5. PIM Kinases in Multiple Myeloma. Wu J, Chu E, Kang Y. Cancers (Basel) 13 4304 (2021)

Articles citing this publication (13)

  1. Privileged Structures Revisited. Schneider P, Schneider G. Angew. Chem. Int. Ed. Engl. 56 7971-7974 (2017)
  2. Acquired savolitinib resistance in non-small cell lung cancer arises via multiple mechanisms that converge on MET-independent mTOR and MYC activation. Henry RE, Barry ER, Castriotta L, Ladd B, Markovets A, Beran G, Ren Y, Zhou F, Adam A, Zinda M, Reimer C, Qing W, Su W, Clark E, D'Cruz CM, Schuller AG. Oncotarget 7 57651-57670 (2016)
  3. Discovery of 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines as potent PIM inhibitors. Wu B, Wang HL, Cee VJ, Lanman BA, Nixey T, Pettus L, Reed AB, Wurz RP, Guerrero N, Sastri C, Winston J, Lipford JR, Lee MR, Mohr C, Andrews KL, Tasker AS. Bioorg. Med. Chem. Lett. 25 775-780 (2015)
  4. Discovery of imidazopyridazines as potent Pim-1/2 kinase inhibitors. Wurz RP, Sastri C, D'Amico DC, Herberich B, Jackson CLM, Pettus LH, Tasker AS, Wu B, Guerrero N, Lipford JR, Winston JT, Yang Y, Wang P, Nguyen Y, Andrews KL, Huang X, Lee MR, Mohr C, Zhang JD, Reid DL, Xu Y, Zhou Y, Wang HL. Bioorg. Med. Chem. Lett. 26 5580-5590 (2016)
  5. Molecular dysfunctions in acute myeloid leukemia revealed by integrated analysis of microRNA and transcription factor. Lin XC, Xu Y, Sun GP, Wen JL, Li N, Zhang YM, Yang ZG, Zhang HT, Dai Y. Int. J. Oncol. 48 2367-2380 (2016)
  6. The discovery and optimization of aminooxadiazoles as potent Pim kinase inhibitors. Wurz RP, Pettus LH, Jackson C, Wu B, Wang HL, Herberich B, Cee V, Lanman BA, Reed AB, Chavez F, Nixey T, Laszlo J, Wang P, Nguyen Y, Sastri C, Guerrero N, Winston J, Lipford JR, Lee MR, Andrews KL, Mohr C, Xu Y, Zhou Y, Reid DL, Tasker AS. Bioorg. Med. Chem. Lett. 25 847-855 (2015)
  7. Discovery of N-substituted 7-azaindoles as PIM1 kinase inhibitors - Part I. Barberis C, Moorcroft N, Arendt C, Levit M, Moreno-Mazza S, Batchelor J, Mechin I, Majid T. Bioorg. Med. Chem. Lett. 27 4730-4734 (2017)
  8. Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors. Naguib BH, El-Nassan HB, Abdelghany TM. J Enzyme Inhib Med Chem 32 457-467 (2017)
  9. Targeting Pim Kinases and DAPK3 to Control Hypertension. Carlson DA, Singer MR, Sutherland C, Redondo C, Alexander LT, Hughes PF, Knapp S, Gurley SB, Sparks MA, MacDonald JA, Haystead TAJ. Cell Chem Biol 25 1195-1207.e32 (2018)
  10. Human CD180 Transmits Signals via the PIM-1L Kinase. Egli N, Zajonz A, Burger MT, Schweighoffer T. PLoS ONE 10 e0142741 (2015)
  11. Design and Synthesis of Novel Pyridine-Based Compounds as Potential PIM-1 Kinase Inhibitors, Apoptosis, and Autophagy Inducers Targeting MCF-7 Cell Lines: In Vitro and In Vivo Studies. Shaban SM, Eltamany EH, Boraei ATA, Nafie MS, Gad EM. ACS Omega 8 46922-46933 (2023)
  12. Design, Synthesis, and In Vitro Activity of Pyrazine Compounds. Parsonidis P, Shaik M, Serafeim AP, Vlachou I, Daikopoulou V, Papasotiriou I. Molecules 24 (2019)
  13. Discovery of N-substituted 7-azaindoles as Pan-PIM kinase inhibitors - Lead series identification - Part II. Barberis C, Moorcroft N, Pribish J, Tserlin E, Gross A, Czekaj M, Barrague M, Erdman P, Majid T, Batchelor J, Levit M, Hebert A, Shen L, Moreno-Mazza S, Wang A. Bioorg. Med. Chem. Lett. 27 4735-4740 (2017)


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