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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5354_Библиотеки_им_академика_М_И_Перельмана
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β- Carbolines
Scientists have been searching for specic inhibitors of IKK to NF- κB. A natural
product derivative called 5- bromo- 6- methoxy- β- C (39) was identied as a nonspecic
IKK inhibitor in an evaluation of the endogenous IKK complex. This discovery led to
the renement of this derivative, yielding a new category of selective IKK inhibitors
with IC50 in the nanomolar range. Among the identied analogs, compound 40
emerged as effective in inhibiting IKK and its downstream signaling pathways both
in cellular and in vivo models. Its capability to hinder the phosphorylation of IκBα,
subsequently blocking NF- κB activation in cells, along with its ability to curtail TNF-
α release in lipopolysaccharide- challenged mice, positions it as a potential candidate
for treating diverse cancers and inammatory conditions. Further investigations are
underway to analyze its efciency and safety in clinical trials (Castro et al. 2003).
Control over nuclear factor (NF)- κB transcription factors plays a pivotal role in
the pathogenesis of numerous diseases. Research aimed to investigate the impact of
a β- C alkaloid (41) on suppressing NF- κB signaling pathways in lipopolysaccharide-
stimulated RAW 264.7 cells. The alkaloid displayed a concentration- dependent reduction in the inducible nitric oxide synthase protein level and NOS promoter activities.
Furthermore, it diminished nuclear translocation, phosphorylation, and degradation
of IκB, NF- κB DNA binding activity, and attenuated IKK activity in LPS- stimulated
RAW 264.7 cells. These ndings indicate the potential of the β- C alkaloid (41) to
inhibit IKK activity, subsequently suppressing the NF- κB signaling pathway in LPS-
stimulated RAW 264.7 cells (Woo Yoon et al. 2005).
β- Cs and their derivatives have shown promising potential as IKK inhibitors.
These compounds could offer a novel approach for developing therapeutic strategies
to address diseases associated with NF- κB pathway dysregulation. Further research
is necessary to elucidate the exact mechanism of action of these compounds and to
rene their pharmacodynamic and pharmacokinetic properties.
4.2.5 β- cArboliNes As iNhibiTors of cDc- liKe KiNAse 1 (clK1)
CDC- like kinase 1 known as CLK1 is a protein kinase that plays a vital role in premRNA splicing by phosphorylating serine- arginine- rich proteins. It also participates
in governing circadian rhythm and apoptosis (Martín Moyano, Němec, and Paruch
2020). CLK1 has been labelled as a potential therapeutic target for diseases such
as viral infections, cancer, and neurological disorders. Inhibition of CLK1 has been
shown to decrease tumour growth, enhance the efcacy of chemotherapy, and inhibit
viral replication (ElHady et al. 2022). Small molecule inhibitors of CLK1 are currently under development and show favorable results as potential therapies for
cancer and other diseases. Different β- C analogs with signicant CLK1 activity are
illustrated in Figure 4.9.
A series of hybrid β- C compounds, amalgamating benzimidazole and benzoxazole
fragments, were synthesized and tested for their anticancer potential against four distinct human tumor cell lines. These hybrids exhibited noteworthy anticancer efcacy
against A549 (lung), MCF- 7 (breast), A2780 (ovarian), and Colo- 205 (colon) cell
lines. Molecular interaction analysis, focusing on cancer cell migration and specic
kinase targets, unveiled their potential binding modes, with certain hybrid β-
C compounds demonstrating selectivity towards CDC- like kinases (CLK- 1 through
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β-Carbolines as Kinase Inhibitors
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FIGURE 4.9 Various β- carbolines with CLK inhibitory activity.
CLK- 4). Combining the thiazole- linked β- C nucleus with the benzimidazole core
notably enhanced the antitumor activity against the former three cell lines, while
the presence of benzoxazole rendered the β- C moderately active. This rationale
was supported by a promising antineoplastic prole observed against MCF- 7 breast
cancer cell lines (Sireesha et al. 2021).
A study introduced a derivative, 7,8- dichloro- 1- oxo- β- Cs, as a versatile frame-
work for non- ATP mimetic kinase inhibitors. The primary component of this compound was derived from the natural complex bauerine C (9), and structure- activity
relationships were validated. The complexes of 4- cyano- 1,2,3,4- tetrahydro- 1- oxo- β- C
type, including spiropiperidine 45, have been shown to possess signicant inhibitory
activity against oncogenic DAPK3 and PIM kinases. X- ray crystallography revealed
their unusual binding mode and good specicity with scarce off- targets outside and
within the AGC (protein kinase A, G ,and C) family. Cellular assays showed that
compound 45 exhibited antiproliferative activity at lower micro- molar concentrations
and depleted PIM- regulated phosphorylation of downstream effector proteins. The Nmethyl analogue 46 demonstrated intriguing binding mode with DAPK3 by forming
halogen bonds with the kinase hinge region, contributing to inhibitor selectivity. The
6,7- dichloroindole scaffold can also serve as a template for new CLK inhibitors, and
selected compounds such as primary amine 47 and alkaloid 9 could be optimized to
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β- Carbolines
generate new targeted inhibitors of DRAK1 and BMP2K (BIKE). Research is currently being conducted to increase the potency and selectivity of these compounds
(Huber et al. 2012).
Overall, these studies demonstrated the prospects of β- Cs and their derivatives as
selective and potent inhibitors of CLK1 and other CLK family members. Additional
studies are necessary to enhance the therapeutic capacity of these compounds and
assess their effectiveness and safety in preclinical and clinical environments.
4.2.6 β- cArboliNes As iNhibiTors of proTeiN KiNAse b (pKb or AKT)
Protein kinase B (PKB), also recognized as Akt kinase, is a serine/ threonine- specic
kinase pivotal in diverse cellular functions. These encompass glucose metabolism,
cell proliferation, transcription, apoptosis, and cell migration (Uko et al. 2020).
Dysregulation of the Akt pathway has been linked to various diseases, including cardiovascular diseases, cancer, and diabetes. Akt inhibitors have been developed as
potential cancer therapeutics, and have shown promising results in preclinical studies
(Bhutani, Sheikh, and Niazi 2013). Additionally, inhibition of Akt has been shown
to reduce oxidative stress and inammation in some neurodegenerative diseases like
Parkinson’s disease and Alzheimer’s disease. Figure 4.10 demonstrated several β- C
compounds that were active against PKB.
FIGURE 4.10 Different β- carbolines having inhibitory activity against PKB.
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β-Carbolines as Kinase Inhibitors
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The β- C alkaloids have remarkable pharmacological properties and can be used to
control plant pathogenic nematodes and pests. However, there is a lack of research on
their potential insecticidal properties. A previous study found that these complexes
can trigger apoptosis in cancer cell lines, which led to further investigation of its
toxicological operations on insects. A recent study focused on examining the cytotoxicity of natural harmala alkaloids (ve in number) and found that they have an
autophagy- inducing effect on the Spodoptera frugiperda Sf9- cultured cell line. The
study unveiled that natural harmala alkaloids demonstrated inhibition of Sf9 cell proliferation, exhibiting dependency on both time and dosage. The study found that two
unsaturated β- C alkaloids, harmol (6) and harmine (1), showed more potent autophagy
induction activity as evidenced by LysoTracker Red and monodansyl cadaverine
staining. The administration of β- C resulted in an elevation in the expression of several autophagy- related genes at the RNA level, accompanied by an increase in the
protein expression of Sf- Atg8 post- treatment. Throughout this investigation, notable
alterations were observed in the core autophagic signaling pathway, specically the
PI3K/ Akt/ mTOR pathway, in response to β- C. To verify this, specic activators and
inhibitors were employed, and the outcomes suggested that the PI3K/ Akt/ mTOR
pathway primarily regulated the induction of autophagy prompted by harmine in
insect cellular models. These discoveries hold potential implications for the utilization of these bioactive components across various domains (Cui et al. 2019).
A novel series of β- Cs that contain hydroxamic acid and are linked through a
hydroxycinnamic acid moiety were proposed as potential antitumor agents. The aim
was to incorporate histone deacetylase (HDAC) inhibition to enhance the potency of
naturally occurring β- Cs, which have limited anticancer activities. The in vitro assays
conducted on these novel β- Cs demonstrated signicant antitumor activities against
four human cancer cell lines. From the series, compound 48 showed the highest cytotoxic potency. Compound 48 was observed to enhance the acetylation levels of histone H3 and α- tubulin in tumor cells. It also induced a high rate of apoptosis as
compared to the reference HDAC inhibitor SAHA. Additionally, it demonstrated
potential autophagic ux activity in Bel7402- cells. Moreover, this compound was
found to signicantly inhibit the PI3K/ Akt/ mTOR signaling route, which is a critical
path for promoting cellular growth and is often activated in various types of cancers.
One of the most remarkable discoveries was its selective inhibition of tumor cell
proliferation, particularly the drug- sensitive Bel7402 and the drug- resistant Bel7402/
5- FU cells, without exerting a signicant effect on normal LO2 cells. Based on the
results of the in vitro assays, it can be suggested that the hydroxamic- acid containing
β- C analogs have the potential quality to be a more effective contender for carcinoma
therapy in humans. The derivatives combine the main structural parts of classical
HDACIs, harmine (1) and HCA, leading to improved efcacy and synergistic effects
or even drug resistance reversal (Ling et al. 2019).
The researchers developed and synthesized a series of HDAC (hydroxamic
acid histone deacetylase) inhibitors by incorporating the β- C motif and exploring
the impact of C3 amide substitution on HDAC inhibition and antiproliferative
activity. Most of these compounds exhibited remarkable HDAC inhibition and
antiproliferative activity, demonstrating IC50 values in the lower micromolar range.
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β- Carbolines
The most potent compound identied in the series, N- (2(dimethylamino) 1 1 ethyl)N- (4- (hydroxylcarbamoyl) 3 37 benzyl)- 1- (4- methoxyphenyl)- 9H pyrido[3,4- b]
indole- 3- carboxamide (49), displayed an HDAC inhibition IC50 value ve times
lower than that of suberoylanilide hydroxamic acid (SAHA, vorinostat). Moreover,
this compound increased the acetylation reaction of histone H3 and α- tubulin.
Alongside its HDAC- inhibitory effects, compound 49 induced DNA damage and
hindered several signaling pathways commonly activated in cancers, including Stat3,
Akt, and ERK. The moderate Caco- 2 cell permeability and reasonable solubility of
compound 49 suggest that β- C- based HDAC inhibitors hold promise as therapeutic
agents for human cancers (Ling et al. 2017).
A set of harmine (1) derivatives was synthesized and studied with a benzylidene
derivative in the 1- position of the β- C ring, aiming to explore their potential as
anticancer agents. The most noteworthy anticancer activities were observed with
the N2- benzylated β- C derivatives, and compound 50 exhibited the highest activity
against various cancer cell lines. It induced apoptosis in cancer cells with minimum
toxicity to normal cells. It also promoted ROS production and inhibited phosphorylation of AKT leading to activation of the mitochondria- dependent cell apoptotic
pathway and suppression of phosphorylated AKT. It also showed promising antitumor
effects in a nude mice xenograft model and has great potential as active therapeutic
agent for cancer treatment (Zhang et al. 2016).
A comprehensive array of 1- substituted and 1,3- disubstituted β- C analogs were
synthesized in a study employing a modied one- step Pictet- Spengler reaction. The
anti- inammatory potential of these synthesized compounds was assessed by their
ability to inhibit the production of NO (nitric oxide) and PGE2 (prostaglandin E2),
alongside evaluating their cellular toxicity against four human cancer cell lines. The
majority of the examined compounds displayed robust inhibitory activity against the
production of NO and PGE2. Notably, compounds 51 and 52 exhibited signicant
reductions in the expression of inducible cyclooxygenase 2 (COX2) and nitric oxide
synthase (iNOS), indicating the capacity of β- C analogs to curtail the production of
these molecules at a translational level. Certain β- C derivatives also demonstrated
noteworthy inhibition of superoxide anion (O
2-
) generation or elastase production
compared to the reference compound, with compound 51 displaying the highest
potency. The synthetic 1- benzoyl- 3- carboxy β- C analogs showcased promising
potential as anti- inammatory drugs. Furthermore, it was observed that these analogs
hindered N- formyl- L- methionyl- phenylalanine (FMLP)- induced phosphorylation of
JNK (c- Jun N- terminal kinase) and AKT (protein kinase B), suggesting their role in
reducing human neutrophil functions by inhibiting the activation of AKT and JNK
signaling pathways (Yang et al. 2011).
In conclusion, β- Cs have shown promising potential as inhibitors of AKT kinase,
a critical signaling molecule involved in numerous cellular processes. Research
has shown their capability to suppress AKT activation and impede cancer cell
growth, rendering them a potential therapeutic target for cancer treatment. Further
investigations are warranted to enhance the efcacy and safety of β- Cs as AKT kinase
inhibitors. However, their distinct chemical properties and mode of action present a
promising avenue for exploration.
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β-Carbolines as Kinase Inhibitors
4.2.7 β- cArboliNes As iNhibiTors of polo- liKe KiNAses (plKs)
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PLKs denote a cluster of serine/ threonine protein kinases overseeing several cellular
functions, such as mitosis, cell cycle progression, cytokinesis, and meiosis. Within
mammals, PLKs serve a pivotal role in overseeing cell division, centriole duplication,
and chromosome segregation (Barr, Silljé, and Nigg 2004). Abnormal expression and
activity of Polo- like kinases (PLKs) were linked to several diseases, including cancer.
As a result, inhibitors targeting PLKs are being investigated as potential therapeutic
agents for cancer treatment. For instance, polo- like kinase 1 (PLK1) inhibitors are
being studied for their potential use in non- small cell lung carcinoma therapy (Zhang
et al. 2021). Additionally, abnormal expression of Polo- like kinase 4 (PLK4) was
observed in various human cancers, proposing a potential role for PLK4 inhibition
in cancer therapy (Garvey et al. 2021). β- C compounds with good PLK inhibitory
activity are demonstrated in Figure 4.11.
The inhibitory activity of PLK- 1 was examined for a library of β- C/ Schiff bases.
Compound 53, from all the synthesized compounds, showed the highest potency
against colon cancer with a GI50 range of 3- 45 μM in the NCI- 60 panel cell assay.
The other compounds also demonstrated strong to mild cytotoxic activity against the
panel cell lines. During Kinome scan screening, it was found that it can target PLK-
1 specically at a concentration of 15 μM. Furthermore, it was observed that when
administered at varying concentrations, it caused a corresponding halt in the cell cycle
progression at S/ G2 phase in HCT- 116 cells. Further, it triggered programmed cell
death by activating procaspase- 3 and cleaved PARP (poly(ADP)ribose polymerase.
Experiments conducted on DLA and EAC animal models indicated that compound
53 administered at 100 mg/ kg/ bd. wt dosage, notably extended the average lifespan
FIGURE 4.11 Several β- carboline derivatives possessing potential PLK inhibitory activity.
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of mice with tumors, demonstrating its potential as an effective antitumour agent.
Despite observing a reduction in the body mass of tumor- enduring mice in comparison
to the tumor- regulated mice, the results from the experiments indicated that
compound 53 possessed the potential to act as an effective antitumor agent (Jeyapal
et al. 2019).
This study aimed to construct and authenticate a model capable of forecasting the
efcacy of 𝛽- C analogs as antitumor agents against HepG2 human cancer cell lines.
Using ALMOND software, an alignment- free 3D- QSAR analysis was conducted to
compute alignment- independent descriptors (known as GRIND descriptors). After
analyzing a training 30- compound set the resulting model achieved a squared correlation coefcient of 0.957 and a standard deviation error of 0.116 in calculations. To
validate the model, both leave- one out and leave- multiple out methods were employed,
which demonstrated a high level of accuracy in predicting results with a 0.66 score
for a test of set consisting ten compounds. In addition, the research study employed
molecular docking techniques to explore the approach used to assess the interaction
between 𝛽- C analogs and the active site of the most probable anticancer receptor, the
PLK protein. According to the research ndings, it was determined that the primary
factors contributing to the antitumor effectiveness of the compounds under investigation were hydrophobicity, shape effects, and hydrogen bond interactions. This
research study offered valuable insights that can facilitate the development of some
novel drugs that target HepG2 cell lines by providing guidance on the design of such
drugs (Ghasemi and Davoudian 2014).
Throughout the study, scientists created a range of β- C derivatives and determined
that three specic compounds, namely 54, 55, and 56, exhibited strong potential as
novel inhibitors of PLK. The compounds synthesized in this research selectively
inhibited the PLK1, PLK2, and PLK3 in vitro kinase activity, and exhibited potent
antitumor properties against multiple cancer cell lines. Additionally, the compounds
induced cell cycle block and cellular death in tumor cells while demonstrating comparably lower levels of toxicity towards noncancer cells. One interesting observation
from the study was that the compounds displayed contrasting levels of sensitivity
between normal and cancer cells. Based on their ndings, the researchers deduced
that β- carboline derivatives 54, 55, and 56 exhibited strong potential as novel PLK
inhibitors and could be considered as potential candidates for cancer treatment.
Further studies will clarify the mechanism contributing to the differences in cell cycle
block induced by these compounds (Han et al. 2012).
The researchers conducted an analysis of the SARs within a collection of β- C
alkaloid analogs through the use of both protein docking and 2D QSAR methodologies. Their goal was to discover the interaction method between PLK1 kinase, and β-
C derivatives as well as ascertain the vital substituents dictating the cytotoxic activity
of these derivatives. The QSAR models demonstrated strong correlations between
the observed and predicted activities of the β- C alkaloid derivatives, highlighting
lipophilicity as a pivotal factor inuencing their cytotoxicity. Molecular docking
studies revealed that ligand 57 displayed elevated binding energy and prociently
interacted with the active sites of the PLK1 kinase through hydrophobic interactions
and hydrogen bonding. These ndings offer insights that can be leveraged to design
novel and more potential β- C derivatives as effective cytotoxic agents. In addition,
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the authors designed three new compounds that were predicted to have fever binding
afnity and enhanced cytotoxic activity. Taken together, these outcomes provide
valuable insights that can be leveraged in virtual screening for novel β- C derivatives
and facilitate the design of new compounds possessing superior biological activities
(Akabli et al. 2018).
A β- C derivative, 58, was determined to be more effective in restraining the proliferation of cdc5- 2 temperature- sensitive mutant yeast cells, which contain a human
PLK1 homologue, than wild- type yeast cells. It was also observed to inhibit puried
PLK1 kinase activity in an ATP- competitive manner at low micromolar concentrations,
as conrmed by docking investigations based on the crystal structure of PLK1. The β-
C derivative demonstrated its ability to inhibit tumor cell proliferation, induce mitotic
block, enhance the cyclin B1 accumulation, and stimulate apoptosis by potentially
downregulating PLK1. These results provide evidence that the cytotoxicity of betacarboline derivatives towards tumor cells may be attributed to PLK1 inhibition, which
is a novel and signicant nding in this eld of research (Zhang et al. 2009).
In conclusion, β- Cs and their derivatives have shown potential as PLK inhibitors,
with preclinical studies showcasing their potential to trigger apoptosis and induce cell
cycle arrest in cancer cells. Further research is required to enhance the efcacy and
safety prole of β- C derivatives acting as PLK inhibitors and to evaluate their potential as anticancer agents in clinical trials.
4.2.8 β- cArboliNes As iNhibiTors of glycogeN syNThAse KiNAse (gsK)
Glycogen synthase kinase labelled as GSK is a serine/ threonine protein kinase with
diverse functions, notably regulating glycogen metabolism and glucose storage
(Buschiazzo et al. 2004). Present in two isoforms, GSK- 3 is primarily located in
neurons within the CNS (central nervous system). It plays a pivotal role in glycogen
metabolism and glucose storage, serving as a key mediator in intracellular signaling
downstream of receptors crucial for neuronal function. Inhibition of GSK- 3 has been
investigated as a potential therapeutic strategy for a range of diseases including bipolar
disorder, AD, and type 2 diabetes. GSK inhibitors can be of different chemotypes,
including non- ATP competitive inhibitors, from natural sources, substrate- competitive
inhibitors, and cations and synthetic ATP (Marosi et al. 2022). Additionally, GSK- 3
is directly regulated by other protein kinases such as AMPK, PKA, and casein kinase
2 (CK2), which led to catalytically inactive and phosphorylated glycogen synthase
(Embi, Rylatt, and Cohen 1980; Proud et al. 1977). β- C derivatives with signicant
GSK inhibitory activity are shown in Figure 4.12.
FIGURE 4.12 β- carbolines with signicant GSK inhibitory activity.
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In a study, the authors identied a novel series of harmine compounds incorporating the N- benzylpiperidine moiety for potential treatment of AD. These derivatives
displayed notable activity against AChE and showed selectivity over BChE. Among
these compounds, compound 59 exhibited strong anti- AChE activity with 0.27 mM
IC50 value and selective BChE inhibition with 20.82 mM IC50 value. Additionally,
it showed moderate GSK- 3 (glycogen synthase kinase- 3) inhibition with an IC50
value of 6.78 mM. Based on ligand- protein docking studies and molecular simulation methods, compound 59 was found to be able to form a stable interaction with
both GSK- 3b and AChE. Additionally, it displayed great selectivity towards GSK- 3b
compared to multikinases and showed low cell toxicity towards SH- SY5Y, HL- 7702
HEK- 293T, and HepG2 cell lines. The authors observed that ZLWH- 23 effectively
decreased tau hyperphosphorylation at the Ser- 396 site in Tau (P301L) 293T cellular framework. Based on these investigations, the authors suggested that derivatives
based on harmine carry the potential to be formulated into drug leads for Alzheimer’s
treatment (Liu et al. 2022).
A group of researchers conducted a screening of a repository of plant extracts to
identify compounds that could inhibit the transcriptional activity of TCF/ β- catenin,
which is a critical element of the Wnt signaling route. From the root extract of
E. longifolia, researchers discovered a compound named 9- hydroxycanthin- 6- one (60)
that showed inhibitory activity against TCF/ β- catenin transcription. The researchers
discovered that compound 1 had the ability to inhibit Wnt signaling by activating
GSK3β without the need for CK1α, a kinase necessary for the initial phosphorylation
of β- catenin. In zebrash embryos, the compound reduced the expression in both Wnt
target genes, and in SW480 cells, it reduced β- catenin levels. Additionally, they found
that compound 60 has a unique mechanism of inducing β- catenin degradation without
the need for phosphorylation by CK1α. Considering these ndings, compound 60
holds promise as a potential lead compound for developing Wnt signal inhibitors
targeting GSK3β (Ohishi et al. 2015).
Additional inquiries are needed to comprehend the mechanisms from which β-
Cs and their derivatives inhibit GSK3, as well as to assess their safety and efcacy
as potential therapeutics. Nevertheless, the inhibition of GSK3 via β- Cs presents a
promising therapeutic approach to manage the diverse diseases linked to dysregulated
GSK3 activity.
4.2.9 β- cArboliNes As iNhibiTors of MiscellANeous KiNAses
Figure 4.13 represents several β- C analogs that were active against several kinases
such as haspin, aurora, B- Raf, Brk, PDGF, and SK1. Haspin kinase, a type of serine/
threonine protein kinase, is signicant in mitosis progression and histone H3 phosphorylation. Researchers have recognized it as a propitious target for developing
anticancer drugs (Amoussou et al. 2018). Depletion of Haspin kinase led to decreased
proliferation and reduced activation of the cGAS (cyclic GMP- AMP synthase)- stimulator of interferon genes pathway (Melms et al. 2020). Different classes of small molecule inhibitors have been created to investigate the mitotic roles of Haspin kinase.
(Wang et al. 2020).
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FIGURE 4.13 Various β- carbolines having different kinases inhibitory activities.
A study focused on identifying potential cancer therapeutic targets by inhibiting
the haspin kinase through screening 140,000 compounds. β- Cs harmine (1) and
harmol (6) were identied as slightly effective inhibitors, and harmine derivatives
were designed to increase inhibitory potency further. The incorporation of a tethered
primary amine and replacement of the methyl group with a triuoromethyl group
yielded compound 61, displaying considerable in vitro metabolic stability in mouse
liver microsomes and moderate selectivity, inhibiting only six kinases in common.
These ndings suggest that compounds from the harmine series, like 61, could serve
as effective molecular tools for exploring the cellular functions of haspin kinase
and potentially hold promise for therapeutic applications in cancer treatment (Cuny
et al. 2012).
Aurora kinases are enzymes that play a critical role in mitosis and are expressed
differentially in rapidly dividing cells. Heightened expression of Aurora kinases
correlates with polyploidy and cancer pathology (Ahmed et al. 2021). Aurora kinases
isoforms A, B, and C plays a crucial role in cellular division and are frequently elevated
in cancer. Due to their signicance, they are attractive targets for treatment. Recently,
a new multitargeted inhibitor of Aurora B kinase, 62, has been developed from an
innovative azacarboline kinase hinge- binder chemotype. It exhibits potent and timedependent inhibition specically targeting Aurora B rather than Aurora A. This inhibition led to repression of histone H3 phosphorylation and induction of polyploidy. It
inhibits the proliferation of diverse human cancer cell lines, displaying effective concentration values spanning from 40 to 500 nmol/ L. In intact cells, it also hinders the
activity of other kinases, such as FLT3 and FGFR2, but not as effectively as Aurora
B. In rodent xenografts, it showed strong efcacy against different types of human
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