Abstract:(-)-Balanol is an adenosine triphosphate mimic that inhibits protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA) with limited selectivity. While PKA is known as a tumor promoter, PKC isozymes can be tumor promoters or suppressors. In particular, PKCε is frequently involved in tumorigenesis and a potential target for anticancer drugs. We recently reported that stereospecific fluorination of balanol yielded a balanoid with enhanced selectivity for PKCε over other PKC isozymes and PKA, althoug… Show more
“…Similar to our previous finding [50], the invariant Lys residue in the ribose subsite has major contribution on the binding of 1c. The behavior of the azepane ring may strengthen or weaken the contribution of the invariant Lys.…”
Section: Discussionsupporting
confidence: 90%
“…The synergy between 1c and the dynamics feature of PKCε results in interactions that are free from unfavorable binding energy (Supporting Information: Fig. S7), explaining the strong binding affinity of 1c to the kinase [ 18 ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“… value was computed from each trajectory of nPKC-bound 1c . Here, we also used PKA-bound 1c trajectory from our previous study [ 50 ] for an additional data point. The resulting values were compared with experiment.…”
Section: Methodsmentioning
confidence: 99%
“…Furthermore, 1c can strengthen its interaction with the invariant Lys437 ( Fig. 5a; Additional file 1: Note 2), which is considered as the most contributing residue in the binding of balanoid to kinases [18]. Balanoid 1c creates a very strong binding energy with the Lys437 (− 16.83 kcal.mol − 1 ; Additional file 1: Figure S7).…”
Section: Dynamics Feature Of Novel Pkc Isozymesmentioning
confidence: 99%
“…Furthermore, this method gives an opportunity to investigate induced-fit interactions in ligand binding [17], since protein kinases possess such plasticity [1]. In our previous work by exploiting the power of MD [18], we revealed an interesting factor causing different binding responses of PKA and PKCε to balanoids. Those different binding responses are contributed by a structurally equivalent residue in each kinase, Thr184 in PKA and Ala549 in PKCε.…”
Background: (−)-Balanol is an ATP-mimicking inhibitor that non-selectively targets protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA). While PKA constantly shows tumor promoting activities, PKC isozymes can ambiguously be tumor promoters or suppressors. In particular, PKCε is frequently implicated in tumorigenesis and a potential target for anticancer drugs. We recently reported that the C5(S)-fluorinated balanol analogue (balanoid 1c) had improved binding affinity and selectivity for PKCε but not to the other novel PKC isozymes, which share a highly similar ATP site. The underlying basis for this fluorine-based selectivity is not entirely comprehended and needs to be investigated further for the development of ATP mimic inhibitors specific for PKCε. Results: Using molecular dynamics (MD) simulations assisted by homology modelling and sequence analysis, we have studied the fluorine-based selectivity in the highly similar ATP sites of novel PKC (nPKC) isozymes. The study suggests that every nPKC isozyme has different dynamics behaviour in both apo and 1c-bound forms. Interestingly, the apo form of PKCε, where 1c binds strongly, shows the highest degree of flexibility which dramatically decreases after binding 1c. Conclusions: For the first time to the best of our knowledge, we found that the origin of 1c selectivity for PKCε comes from the unique dynamics feature of each PKC isozyme. Fluorine conformational control in 1c can synergize with and lock down the dynamics of PKCε, which optimize binding interactions with the ATP site residues of the enzyme, particularly the invariant Lys437. This finding has implications for further rational design of balanol-based PKCε inhibitors for cancer drug development.
“…Similar to our previous finding [50], the invariant Lys residue in the ribose subsite has major contribution on the binding of 1c. The behavior of the azepane ring may strengthen or weaken the contribution of the invariant Lys.…”
Section: Discussionsupporting
confidence: 90%
“…The synergy between 1c and the dynamics feature of PKCε results in interactions that are free from unfavorable binding energy (Supporting Information: Fig. S7), explaining the strong binding affinity of 1c to the kinase [ 18 ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“… value was computed from each trajectory of nPKC-bound 1c . Here, we also used PKA-bound 1c trajectory from our previous study [ 50 ] for an additional data point. The resulting values were compared with experiment.…”
Section: Methodsmentioning
confidence: 99%
“…Furthermore, 1c can strengthen its interaction with the invariant Lys437 ( Fig. 5a; Additional file 1: Note 2), which is considered as the most contributing residue in the binding of balanoid to kinases [18]. Balanoid 1c creates a very strong binding energy with the Lys437 (− 16.83 kcal.mol − 1 ; Additional file 1: Figure S7).…”
Section: Dynamics Feature Of Novel Pkc Isozymesmentioning
confidence: 99%
“…Furthermore, this method gives an opportunity to investigate induced-fit interactions in ligand binding [17], since protein kinases possess such plasticity [1]. In our previous work by exploiting the power of MD [18], we revealed an interesting factor causing different binding responses of PKA and PKCε to balanoids. Those different binding responses are contributed by a structurally equivalent residue in each kinase, Thr184 in PKA and Ala549 in PKCε.…”
Background: (−)-Balanol is an ATP-mimicking inhibitor that non-selectively targets protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA). While PKA constantly shows tumor promoting activities, PKC isozymes can ambiguously be tumor promoters or suppressors. In particular, PKCε is frequently implicated in tumorigenesis and a potential target for anticancer drugs. We recently reported that the C5(S)-fluorinated balanol analogue (balanoid 1c) had improved binding affinity and selectivity for PKCε but not to the other novel PKC isozymes, which share a highly similar ATP site. The underlying basis for this fluorine-based selectivity is not entirely comprehended and needs to be investigated further for the development of ATP mimic inhibitors specific for PKCε. Results: Using molecular dynamics (MD) simulations assisted by homology modelling and sequence analysis, we have studied the fluorine-based selectivity in the highly similar ATP sites of novel PKC (nPKC) isozymes. The study suggests that every nPKC isozyme has different dynamics behaviour in both apo and 1c-bound forms. Interestingly, the apo form of PKCε, where 1c binds strongly, shows the highest degree of flexibility which dramatically decreases after binding 1c. Conclusions: For the first time to the best of our knowledge, we found that the origin of 1c selectivity for PKCε comes from the unique dynamics feature of each PKC isozyme. Fluorine conformational control in 1c can synergize with and lock down the dynamics of PKCε, which optimize binding interactions with the ATP site residues of the enzyme, particularly the invariant Lys437. This finding has implications for further rational design of balanol-based PKCε inhibitors for cancer drug development.
Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract, often accompanied by poor prognosis and high incidence and mortality. p21 activated kinases (PAKs) have been used as therapeutic targets because of their central role in many oncogenic signaling networks. By exploring tumor databases, we found that PAK1 overexpression is associated with poor prognosis in colorectal cancer, and therefore, PAK1‐targeted inhibition is a new potential therapeutic strategy for colorectal cancer. We identified that Balanol (compound 6, DB04098) can effectively target PAK1 by high‐throughput virtual screening. In vitro, compound 6 exhibited favorable PAK1 inhibition with potent anti‐proliferative and anti‐migration activity in SW480 cells. Additionally, we also found that compound 6 induced apoptosis and cytoprotective autophagy in SW480 cells. Together, these results indicate that compound 6 is a potential novel PAK1 inhibitor, which would be utilized as a candidate compound for future CRC treatment.
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