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SUMMARY:Structure-Based Discovery of KRAS Inhibitors
DTSTART;VALUE=DATE-TIME:20260327T123000Z
DTEND;VALUE=DATE-TIME:20260327T125000Z
DTSTAMP;VALUE=DATE-TIME:20260426T030136Z
UID:indico-contribution-10319@events.saip.org.za
DESCRIPTION:Speakers: Amanuel Getahun Addis (Bahir Dar University)\n**Abst
 ract**\nKristen rat sarcoma (KRAS) is an oncogene responsible for almost 2
 0% of all human cancers and over  90% of pancreatic ductal adenocarcinoma.
  To date\, only two covalent drugs are approved by the United States food 
 and drug administration (FDA) for the treatment of  KRAS G12C related canc
 ers. However\, their effectiveness is limited in cancers driven by non-G12
 C KRAS mutations as they rely on covalent bonding to the mutant Cys12. On 
 top of that\, the emergence of  resistance to allele-specific inhibitors h
 as shifted substantial effort toward developing noncovalent KRAS inhibitor
 s. As a result\,  several noncovalent inhibitors are in clinical trials\, 
 yet none has been approved for market use\,  underscoring the need for new
  inhibitors. In this study\, we reported small molecules that show a promi
 sing micromolar anti-proliferation activity against pancreatic cancer cell
  lines. The investigated compounds are mainly amine-containing heterocycle
 s with scaffolds that are distinct from those found in existing drugs or l
 ead molecules.The molecules were identified through a structure-based drug
  design campaign on a physicochemically tailored 3D ligand library against
  switch II pocket of KRAS mutants. Based on their micromolar activity\, ex
 tensive interactions in predicted binding modes\, and analyses of structur
 al and physicochemical features\, we propose that these active hits can se
 rve as a starting point for the future characterization and optimization o
 f pan-KRAS inhibitors with broad efficacy. Moreover\, our work demonstrate
 s the proof of concept for using virtual screening in noncovalent drug dis
 covery to benefit from abundant 3D structures of drug-like molecules and t
 he growing database of experimental protein structures\, especially when c
 omputational resources are limited.\n\n**Keywords**: KRAS drug discovery\,
  virtual screening\, molecular docking\, cell growth assay\n\n* *Correspon
 dence to*: amanuel.getahun@bdu.edu.et\n\nhttps://events.saip.org.za/event/
 272/contributions/10319/
LOCATION:
URL:https://events.saip.org.za/event/272/contributions/10319/
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