RNA polymerases synthesize RNA and are targets for cancer drugs. RNA polymerase I synthesizes rRNA precursors, polymerase II synthesizes mRNA and other RNA precursors, and polymerase III synthesizes tRNA and other small RNAs. Several drugs have been developed that target one or more of the human RNA polymerases to inhibit transcription, including CX-5461, metarrestin, α-amatinin conjugates, BMH-21, and TAS-106. CDK inhibitors like palbociclib, ribociclib, abemaciclib and alvocidib (flavopiridol) control the cell cycle by preventing phosphorylation of transcription factors and are used as cancer therapies. RAS

1. RNA Polymerase Inhibitors
• RNA POL I: synthesizes precursors of rRNA.
• RNA POL II: synthesizes precursors of
mRNA, snRNA, miRNAs.
• RNA POL III: synthesizes precursors of tRNA
and other small RNAs.
• Cancer drugs have been developed to
target all three human RNA
polymerases.
• There have been efforts to convert
RNA POL inhibitors into a cancer drug
by combining it with antibodies for
specificity.
Examples:
• CX-5461
• Metarrestin
• α-amatinin Conjugates
• BMH-21
• TAS-106

2. Metarrestin:
• functions by impairing Pol I-ribosomal DNA interaction and inhibiting the function
of Pol I
• It also inhibits the transcription of Pol I and disrupts the function of the
perinuclear compartment which is a complex nuclear structure associated with
metastatic cancer
• some of the functions of metarrestin
are mediated by its binding to the
translation elongation factor eEF1A.

3. α-amatinin Conjugates:
It inhibits both Pol II &Pol III ,thus also the transcription process.
BMH-21:
It is a DNA intercalator which binds rDNA & inhibits RNA POL I transcription.
TAS-106 :
It is a nucleoside analog that inhibits RNA POL I,II.

4. Premature transcription chain terminators
• PTCT refer to a molecular mechanism that can terminate RNA synthesis
prematurely during transcription.
• Transcription is terminated when specific ending codons are reached on the
DNA and after it the mRNA transcript unbinds from the RNA polymerase.
• Cleavage and addition of poly-adenosine chain
• Disturbance by mimicking of adenosine or fludarbine

5. ADENOSINE ANALOGS
• Design to mimic the structural / function of adenosine
• Two modified versions :
•
• 1) 8 CHLOROADENOSINE
• Synthetic compound
• CL atom replace H atom at 8th position
• Help in acute myeloid leukemia and
• chronic lymphocytic leukemia.
• Block the Bcl 2 protein.

6. • 2) 8 AMINO ADENOSINE
• Naturally occurring compound
• NH2 added to 8th position of adenosyl ring.
If both together incorporated
• Inhibit the further synthesis of transcript
• Adenosyl kinase
• Non- cyotoxic for non- transformed cells .

7. FLUDARABINE
• Belongs to antibiotics
• Used in leukemia and lymphomas
• It is prodrug get converted into activemetabolites i.e. 9 beta D- arabinosyl -
2 – fluroadenine.
• Fluridarabine triphosphate or F- ara- ATP
• Inhibits DNA ligase and DNA primase , potassium channels.
• Kill the cancel cells
• Cytotoxicity depend on cell type

8. • 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

9. • It is a selective inhibitor of CDK 4 and
CDK 6 ( causes cell arrest)
• First inhibitor of CDK that was approved
as a cancer therapy in combination with
letrozole, an aromatase inhibitor
• Beneficial effects with combination with
hormone therapy in estrogen receptor +ve
breast cancer
• Adverse effect to patient – Neutropenia
( can be avoided by intermittent dosage)
• Granted palbociclib the breakthrough
therapy designated from FDA in 2013
• It is a semisynthetic flavonoid
• It inhibits CDK 1 ,CDK 2, CDK 4,
CDK 6 and CDK9
• First CDK inhibitor to reach clinical
trial in1998
• Positive results for leukemia and
lymphoma( clinical trial Phase I and II)
Alvocidib (Flavopiridol) Palbocicilib

10. • 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

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

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

13. 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

14. 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
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15. 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.

16. • 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

17. 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.

18. 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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