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

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, Joseph V. Haas, Ellen Cannady, Anthony Borel, Albert E. Schultze, J. Michael Sauder, Jörg Hendle, Ken Weichert, Stephen J. Nicholls and Laura F. Michael ()
Additional contact information
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

Nature, 2024, vol. 629, issue 8013, 945-950

Abstract: 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).

Date: 2024
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DOI: 10.1038/s41586-024-07387-z

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