This document discusses cyclin-dependent kinases (CDKs) and their role in controlling the cell cycle. It provides examples of CDKs that are present at different cell cycle phases, and how CDK inhibitors like abemaciclib work by preventing phosphorylation of transcription factors and uncontrolled cell growth. The document also discusses mTOR signaling pathways and how they regulate processes like protein synthesis, influencing cell proliferation and survival. Targeting central processes like transcription, translation and the cell cycle through CDK and mTOR inhibitors provides more directed cancer treatment while being less toxic than chemotherapy.

1. • Alvocidib
(Flavopiridol)
• Palbociclib
• Ribociclib
• Abemaciclib
• CDKs controls the cell cycle
progression by preventing
phosphorylation of transcription
factors.
• Low amount of CDK and cyclins
does not allow cell to progress to next
phase of cell cycle
• High amount of CDK and cyclin
results in uncontrolled
growth( tumor).
• Different CDKs are present at
different stages of cell cyclee.
Thus , specific CDK targeting is more
beneficial
Cyclin-dependent kinases CDK Inhibitors
Example of CDK
At early G1 :
CDK 4 and CDK 6
End of G1:
CDK2
At S phase :
CDK 2
CDK 1
At G2 phase:
CDK 1

2. • It gained FDA approval in 2017
• Abemaciclib has similar mechanism of
action and usage in cancer treatment for
ER positive cancers as palbociclib and
ribociclib
• Instead of neutropenia it has adverse
effects on gastro-intestinal tract
• It can be continuously taken
• Second selective CDK4/CDK6 inhibitor to
gain market approval as a cancer therapy
in combination with an aromatase inhibitor
• Similar efficacy to palbociclib with similar
toxicity profile
• Ribociclib shown positive effects in high
risk early-stage ER positive breast cancer
Ribociclib Abemaciclib

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

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

5. 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

6. 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

7. 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.

8. • 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

9. 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.

10. 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
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