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Discovery of potent small-molecule inhibitors of lipoprotein(a) formation

Author

Listed:
  • Nuria Diaz

    (Lilly Research Laboratories)

  • Carlos Perez

    (Lilly Research Laboratories)

  • Ana Maria Escribano

    (Lilly Research Laboratories)

  • Gema Sanz

    (Lilly Research Laboratories)

  • Julian Priego

    (Lilly Research Laboratories)

  • Celia Lafuente

    (Lilly Research Laboratories)

  • Mario Barberis

    (Lilly Research Laboratories)

  • Luis Calle

    (Lilly Research Laboratories)

  • Juan Felix Espinosa

    (Lilly Research Laboratories)

  • Birgit T. Priest

    (Lilly Research Laboratories)

  • Hong Y. Zhang

    (Lilly Research Laboratories)

  • Amanda K. Nosie

    (Lilly Research Laboratories)

  • Joseph V. Haas

    (Lilly Research Laboratories)

  • Ellen Cannady

    (Lilly Research Laboratories)

  • Anthony Borel

    (Lilly Research Laboratories)

  • Albert E. Schultze

    (Lilly Research Laboratories)

  • J. Michael Sauder

    (Lilly Research Laboratories)

  • Jörg Hendle

    (Lilly Research Laboratories)

  • Ken Weichert

    (Lilly Research Laboratories)

  • Stephen J. Nicholls

    (Monash University)

  • Laura F. Michael

    (Lilly Research Laboratories)

Abstract

Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a))1,2. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (KIV) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. 3–7). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) KIV7–8. We identify compounds that bind to apo(a) KIV7–8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329—which is already in phase 2 studies—as a potent and specific orally administered agent for reducing the levels of Lp(a).

Suggested Citation

  • Nuria Diaz & Carlos Perez & Ana Maria Escribano & Gema Sanz & Julian Priego & Celia Lafuente & Mario Barberis & Luis Calle & Juan Felix Espinosa & Birgit T. Priest & Hong Y. Zhang & Amanda K. Nosie & , 2024. "Discovery of potent small-molecule inhibitors of lipoprotein(a) formation," Nature, Nature, vol. 629(8013), pages 945-950, May.
  • Handle: RePEc:nat:nature:v:629:y:2024:i:8013:d:10.1038_s41586-024-07387-z
    DOI: 10.1038/s41586-024-07387-z
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