BEGIN:VCALENDAR
VERSION:2.0
PRODID:-//Talks.cam//talks.cam.ac.uk//
X-WR-CALNAME:Talks.cam
BEGIN:VEVENT
SUMMARY:MK-7602: A Promising Breakthrough in Antimalarial Invention from a
 n Efficient Academia/Industry Collaboration - Dr Manuel Ruiz\, Merck
DTSTART:20241118T160000Z
DTEND:20241118T170000Z
UID:TALK212047@talks.cam.ac.uk
CONTACT:111982
DESCRIPTION:Malaria is a devastating disease that affects over half a mill
 ion people each year mostly children under five years old and pregnant wom
 en.\nAntimalarial drug discovery by and large is focused on the identifica
 tion of novel drugs to treat and prevent the disease due to the emergence 
 and spread of Plasmodium strains resistant to existing medicines. In parti
 cular arteminisin resistance which has now spread from South East Asia and
  is firmly established in Africa (as reported at ASTMH in Seattle Oct 2022
 ).\nThe Merck Research Labs (led by Dr. David Olsen) and the Walter and El
 iza Hall Institute of Medical Research (WEHI) (led by Prof. Alan Cowman)\,
  have teamed up to invent novel drug candidates by targeting the Plasmodiu
 m parasite via newly identified essential aspartyl proteases.  The team ha
 s been greatly assisted in this endeavor  with generous funding for the co
 llaboration from the Wellcome Trust (UK).  The team was successful at iden
 tifying potent dual protease targeting hits that lead to the identificatio
 n of an important tool compound WM382 with subnanomolar inhibitory potency
  in vitro. This was accomplished through targeted phenotypic screening and
  structure-guided medicinal chemistry to optimize orphan (mechanism of act
 ion unknown) hit compounds. WM382 was also used to establish impressive in
  vivo proof-of-concept efficacy not only on blood stage parasitemia but al
 so potent pharmacodynamic effects in the sexual/mosquito and liver stages 
 of replication. Finally\, Justin Boddey’s team at WEHI determined that d
 efective parasites under WM382 drug coverage yield some interesting immuno
 logical effects in mice in vivo. Further optimization of potency and pharm
 acokinetic and selectivity profiles resulted in the invention of clinical 
 compound MK-7602\, a very potent PMIX/X dual inhibitor with robust in vivo
  efficacy in mice at the three stages of the malaria parasite lifecycle an
 d excellent off-target activity and resistance profiles.\n\nPublications r
 elated to this work:\n1. The Invention of WM382\, a Highly Potent PMIX/X D
 ual Inhibitor toward the Treatment of Malaria (journal cover shown above).
 \n2. Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages
  of the Malaria Parasite Life Cycle.\n3. Basis for drug selectivity of pla
 smepsin IX and X inhibition for Plasmodium falciparum and vivax.\n\nBio:\n
 Manuel de Lera Ruiz Bio:\nManuel de Lera Ruiz received his B.Sc. in Organi
 c Chemistry from the Universidad Autónoma of Madrid in 1997. After comple
 tion of his Ph.D. in 2001 from the University of Nottingham\, U.K. he join
 ed Professor Leo A. Paquette research labs at Ohio State University as a p
 ostdoctoral fellow. In 2003\, he started a career in Medicinal Chemistry a
 t Schering-Plough Research Institute in New Jersey. Manuel moved to Merck'
 s West Point site in 2012 where he worked for three and a half years in Di
 scovery Process Chemistry. In 2016 he moved back to medicinal chemistry at
  West Point where he is currently a Principal Scientist in Discovery Chemi
 stry co-leading the Malaria plasmepsin inhibitors program.\n
LOCATION:Dept. of Chemistry\, Wolfson Lecture Theatre
END:VEVENT
END:VCALENDAR