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
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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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.
