研究砸钱大兵团?

研究砸钱大兵团?

Failure of cocktail approach aimed at multiple targets simultaneously tells you that superb computer and giant teams (54 authors) won't work! It's fascinating to tell you, big money don't promote science research (see this Merck paper below). Lesson repeats until learned! Merck's Cox-1 inhibitors and HIV inhibitors failed  - they didn't learn though.
 

cocktail approach concept worked once for David Ho, MD (Rockefeller Univ.) for HIV, making him on the cover of TIME, the scientist of the Year in Science (Journal Magazine).

All in common? You're dealing with human body, the line between bad/good is so thin that you scale is delicate - it can go either way out of the boundary of good/bad. So?

**
Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy

By Robert W. Myers, Hong-Ping Guan, Juliann Ehrhart, Aleksandr Petrov, Srinivasa Prahalada, Effie Tozzo, Xiaodong Yang, Marc M. Kurtz, Maria Trujillo, Dinko Gonzalez Trotter, Danqing Feng, Shiyao Xu, George Eiermann, Marie A. Holahan, Daniel Rubins, Stacey Conarello, Xiaoda Niu, Sandra C. Souza, Corin Miller, Jinqi Liu, Ku Lu, Wen Feng, Ying Li, Ronald E. Painter, James A. Milligan, Huaibing He, Franklin Liu, Aimie Ogawa, Douglas Wisniewski, Rory J. Rohm, Liyang Wang, Michelle Bunzel, Ying Qian, Wei Zhu, Hongwu Wang, Bindu Bennet, Lisa LaFranco Scheuch, Guillermo E. Fernandez, Cai Li, Michael Klimas, Gaochao Zhou, Margaret van Heek, Tesfaye Biftu, Ann Weber, David E. Kelley, Nancy Thornberry, Mark D. Erion, Daniel M. Kemp, Iyassu K. Sebhat

Science04 Aug 2017 : 507-511 Full AccessRestricted Access

In animals, a drug activating all 12 isoforms of the energy regulator AMPK benefits metabolism but may pose heart risks.

 

Hitting a dozen enzymes with one drug

The adenosine monophosphate-activated protein kinase (AMPK) controls cellular energy status. AMPK is activated when energy levels fall. This stimulates adenosine triphosphate (ATP)-generating pathways that promote glucose uptake and inhibits ATP-consuming pathways associated with glucose synthesis. In principle, these effects would be beneficial in metabolic diseases, including diabetes. Pharmacological activation of AMPK has been challenging, however, because in mammals, the enzyme exists as 12 distinct complexes. Myers et al. describe an orally available compound (MK-8722) that activates all 12 complexes (see the Perspective by Hardie). In animal models, MK-8722 ameliorated diabetes, but it also caused enlargement of the heart. MK-8722 may be a useful tool compound for laboratory research on AMPK function.

Science, this issue p. 507; see also p. 455

• ↵‡ Address all reagent requests to [e-mail].

http://www.sciencemag.org/about/science-licenses-journal-article-reuse

Abstract

5′-Adenosine monophosphate–activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722–mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.

• ↵‡ Address all reagent requests to [e-mail].
  
   

  1. Robert W. Myers¹,*,†,
  2. Hong-Ping Guan²,*,
  3. Juliann Ehrhart³,
  4. Aleksandr Petrov²,
  5. Srinivasa Prahalada³,
  6. Effie Tozzo²,
  7. Xiaodong Yang²,
  8. Marc M. Kurtz¹,
  9. Maria Trujillo⁴,
  10. Dinko Gonzalez Trotter⁵,
  11. Danqing Feng⁶,
  12. Shiyao Xu⁷,
  13. George Eiermann⁴,
  14. Marie A. Holahan⁵,
  15. Daniel Rubins⁵,
  16. Stacey Conarello⁴,
  17. Xiaoda Niu¹,
  18. Sandra C. Souza²,‡,
  19. Corin Miller⁵,
  20. Jinqi Liu²,
  21. Ku Lu²,
  22. Wen Feng¹,
  23. Ying Li²,
  24. Ronald E. Painter¹,
  25. James A. Milligan¹,
  26. Huaibing He⁷,
  27. Franklin Liu²,
  28. Aimie Ogawa¹,
  29. Douglas Wisniewski¹,
  30. Rory J. Rohm²,
  31. Liyang Wang¹,
  32. Michelle Bunzel⁵,
  33. Ying Qian²,
  34. Wei Zhu²,
  35. Hongwu Wang⁶,
  36. Bindu Bennet³,
  37. Lisa LaFranco Scheuch³,
  38. Guillermo E. Fernandez³,
  39. Cai Li⁴,
  40. Michael Klimas⁵,
  41. Gaochao Zhou¹,
  42. Margaret van Heek⁴,
  43. Tesfaye Biftu⁶,
  44. Ann Weber⁶,
  45. David E. Kelley²,
  46. Nancy Thornberry²,
  47. Mark D. Erion²,
  48. Daniel M. Kemp²,
  49. Iyassu K. Sebhat⁶,†

  1. ¹In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
  2. ²Biology-Discovery, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
  3. ³Safety Assessment and Laboratory Animal Resources, Merck Research Laboratories, West Point, PA 19486, USA.
  4. ⁴In Vivo Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
  5. ⁵Translational Imaging and Biomarkers Departments, Merck Research Laboratories, West Point, PA 19486, USA.
  6. ⁶Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
  7. ⁷PPDM Preclinical ADME Departments, Merck Research Laboratories, Kenilworth, NJ 07033, USA.

  1. ↵†Corresponding author. Email: [e-mail] (R.W.M.); [e-mail] (I.K.S.)

  1. ↵* These authors contributed equally to this work.

  + See all authors and affiliations

  Science  04 Aug 2017:
  Vol. 357, Issue 6350, pp. 507-511
  DOI: 10.1126/science.aah5582