FTR5654

1. CANCER
POINT MUTATIONS
DNA AMPLIFICATION
EPIGENETIC MUTATIONS
CHROMOSOMAL
REARRANGEMENT
MUTATIONS CAUSE
ACTIVATION OF ONCOGENES
INACTIVATION OF TUMOUR
SUPRESSOR GENES

2. RAS
Growth factor receptor
Activated
P
P
P
Transcription factor
activated
P
Cyclin , CDK
RAS GENE’S GENERAL WORKING

3. RAS PROTEINS
 RAS is a group of proteins that include – KRAS, KRASB, HRAS, NRAS.
 These proteins are GTPases that remove gamma phosphate of GTP to give GDP.
 About 89% of human cancers are caused by KRAS G12C mutations.
 G12C = A single point mutation with a glycine-to-cysteine substitution at codon 12.
 G12C mutations makes KRAS lose its GTPase activity .
 This locks KRAS in the GTP bound state and it remains
active.
 The mutant cysteine KRAS G12C creates a narrow pocket
that is susceptible to targeting.
 It is hypothesized that an adjacent histidine 95 (H95) residue may
provide a site to stabilize drug-protein interactions.
 Sotorasib and Adagrasib bind covalently to
cysteine.
 These inhibitors lock KRAS G12C in inactive state
thereby blocking the oncogenic signalling.
Sotorasib Adagrasib

4. mTOR
• mTOR: Mammalian target of rapamycin
• Regulates: Cell proliferation, autophagy, gene transcription, protein, lipid, nucleotide
synthesis, immune cell differentiation.
• Associates: Cancer, tumor metabolism, insulin resistance other diseases.
• “Rapamycin can affect translation by inhibiting the activity of mTOR, a protein kinase that
plays a crucial role in regulating protein synthesis”.
I Want to enter
in mTOR
pathway
R

5. mTORC1
mTOR
mTORC2
Raptor GβL
Deptor
Rictor
GβL Deptor
PRR5
SIN1
• The mTOR complexes affect translation by phosphorylation of multiple translation factors, including eIF4G.
• The mTOR gene itself mutated in cancer.

6. • mTORC1 is the complex that is primarily inhibited by rapamycin, and it is involved in
regulating protein synthesis, autophagy, and lipid metabolism.
• mTORC2, involved in regulating cell survival, proliferation, and metabolism.
• mTOR is involved in a variety of signaling pathways that regulate cellular metabolism,
growth, and survival.
mTOR
PI3K/Akt-
pathways
mTOR
C1
Increase protein synthesis
and cell growth
P
mTOR
AMPK
pathways
mTOR
C1
decrease protein
synthesis
mTOR
mTOR
TGF
β pathways
Insulin
pathways
mTOR
C1
Increases protein
synthesis
mTOR
C1
Increased protein synthesis
and lipid synthesis

7. CONCLUSIONS
• Targeting these central cellular processes has
advantage to be more directed to cancer cells than
non-specific chemotherapeutics agents.
• On the side disadvantages, targeting transcription
and translation may affect multiple pathways.
• Probability of killing healthy cells is lower with
targeted therapies than with the general
chemotherapeutics.
• The role of CDK inhibitor are not limited to cancer
diseases but also other diseases such as in HIV.
• The large number of proteins involved will
continue to provide drug development possibilities
far into the future so that specific and effective
treatment can be achieved.

8. References:
• https://pubmed.ncbi.nlm.nih.gov//
• https://youtu.be/1mo80kTZgW4
• https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-
020-00396-1
• https://www.medchemexpress.com/cx-5461.html
THANK YOU