Identification of quinones as novel PIM1 kinase inhibitors

Schroeder, Richard L.; Goyal, Navneet; Bratton, Melyssa R.; Townley, Ian K.; Pham, Nhu-An; Phan, Tram; Stone, Treasure; Geathers, Jasmine; Nguyen, Kathy; Sridhar, Jayalakshmi

doi:10.1016/j.bmcl.2016.04.079

Cited by 12 publications

(11 citation statements)

References 41 publications

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“…To date, most efforts to inhibit PIM in cancer treatment have focused on a monotherapeutic approach, generally using ATP (adenosine triphosphate)-competitive drugs that target the kinase action of the protein, preventing it from phosphorylating its downstream effectors, either through quinones or other classes of small molecule inhibitors [43][44][45] (Table 1).…”

Section: Pim Inhibition As a Monotherapymentioning

confidence: 99%

“…51 A series of quinone analogs have been shown to offer selective inhibition of PIM, leading to attenuation of growth in the PCa cell line DU145. 43 The PIM selective inhibitor DHPCC-9 impairs the antiapoptotic effects of PIM1 and inhibits the intracellular phosphorylation of PIM substrates, including BAD, leading to reduced invasion and migration in PCa models. 30 Another small molecule PIM inhibitor, SMI-4a, has been well studied in hematological malignancies, where it has been shown to induce apoptosis and has been recommended for study in PCa models.…”

Section: Pim Inhibition As a Monotherapymentioning

confidence: 99%

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PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

Luszczak

Kumar

Sathyadevan

et al. 2020

Sig Transduct Target Ther

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PIM kinases have been shown to play a role in prostate cancer development and progression, as well as in some of the hallmarks of cancer, especially proliferation and apoptosis. Their upregulation in prostate cancer has been correlated with decreased patient overall survival and therapy resistance. Initial efforts to inhibit PIM with monotherapies have been hampered by compensatory upregulation of other pathways and drug toxicity, and as such, it has been suggested that co-targeting PIM with other treatment approaches may permit lower doses and be a more viable option in the clinic. Here, we present the rationale and basis for cotargeting PIM with inhibitors of PI3K/mTOR/AKT, JAK/STAT, MYC, stemness, and RNA Polymerase I transcription, along with other therapies, including androgen deprivation, radiotherapy, chemotherapy, and immunotherapy. Such combined approaches could potentially be used as neoadjuvant therapies, limiting the development of resistance to treatments or sensitizing cells to other therapeutics. To determine which drugs should be combined with PIM inhibitors for each patient, it will be key to develop companion diagnostics that predict response to each co-targeted option, hopefully providing a personalized medicine pathway for subsets of prostate cancer patients in the future.

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Section: Pim Inhibition As a Monotherapymentioning

confidence: 99%

Section: Pim Inhibition As a Monotherapymentioning

confidence: 99%

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

Luszczak

Kumar

Sathyadevan

et al. 2020

Sig Transduct Target Ther

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“…Since the identification of staurosporine and bisindolylmaleimides [ 18 ], a great deal of scientific endeavors have been devoted to the discovery of structurally diverse PIM1 inhibitors. They include imidazo[1,2-b]pyridazine [ 19 ], benzoisoxazole [ 20 ], thiazolidinone [ 21 ], cinnamic acid [ 22 ], benzofuranone [ 23 , 24 ], picolinamide [ 25 ], 4-azapodophyllotoxin [ 26 ], quinone [ 27 ], and azaindole [ 28 ] moieties as the molecular core. Complementary to the experimental discovery, computational studies for PIM1–inhibitor complexes have also been actively pursued by means of quantitative structure–activity relationship [ 29 , 30 ], docking simulations [ 31 ], and quantum chemical calculations [ 32 ] to seek the rationale for inhibitory activities.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Virtual Screening and De Novo Design of PIM1 Inhibitors with Anticancer Activity from Natural Products

et al. 2021

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Background: the proviral insertion site of Moloney murine leukemia (PIM) 1 kinase has served as a therapeutic target for various human cancers due to the enhancement of cell proliferation and the inhibition of apoptosis. Methods: to identify effective PIM1 kinase inhibitors, structure-based virtual screening of natural products of plant origin and de novo design were carried out using the protein–ligand binding free energy function improved by introducing an adequate dehydration energy term. Results: as a consequence of subsequent enzyme inhibition assays, four classes of PIM1 kinase inhibitors were discovered, with the biochemical potency ranging from low-micromolar to sub-micromolar levels. The results of extensive docking simulations showed that the inhibitory activity stemmed from the formation of multiple hydrogen bonds in combination with hydrophobic interactions in the ATP-binding site. Optimization of the biochemical potency by chemical modifications of the 2-benzylidenebenzofuran-3(2H)-one scaffold led to the discovery of several nanomolar inhibitors with antiproliferative activities against human breast cancer cell lines. Conclusions: these new PIM1 kinase inhibitors are anticipated to serve as a new starting point for the development of anticancer medicine.

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“…Ring-opening reaction of anhydride by 1,4-dimethoxybenzene was used by Sridhar to synthesize quinone in three steps by an initial ring opening followed by a Krapcho decarboxylation strategy (Scheme 18). 30 The final product was found to have similar kinase inhibitory activity as emodin 31 against PIM1 kinase, which is responsible for acute myeloid leukemia and prostate cancer in mice.…”

Section: Short Review Synthesismentioning

confidence: 93%

Synthetically Important Ring-Opening Acylations of Alkoxybenzenes

Talukdar¹

2020

Synthesis

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Cyclic ketones, anhydrides, lactams and lactones are a particular class of molecules that are often used in synthesis, wherein their electrophilic properties are leveraged to enable facile Friedel–Crafts ring openings through nucleophilic attack at the carbonyl sp2 centre. The use of electron-rich alkoxybenzenes as nucleophiles has also become important since the discovery of the Friedel–Crafts reaction. As a result, various isomeric alkoxybenzenes are used for preparing starting materials in target-oriented syntheses. This review covers the instances of different alkoxybenzenes that are used as nucleophiles in ring-opening acylations with carbonyl-containing cyclic electrophiles, for the construction of important building blocks for multistep transformations. This review summarizes the ring-opening functionalization of three- to seven-membered molecular rings with alkoxybenzenes in a Friedel–Crafts fashion. Sometimes the rings need subtle or considerable activation by the help of Lewis acid(s), followed by nucleophilic attack. This review is aimed to be a summary of the important acylations of electron-rich alkoxybenzenes by nucleophilic ring-opening of cyclic molecules. The works cited employ a wide range of conditions and differently substituted substrates for target-oriented syntheses.1 Introduction and Scope2 Arenes for Acylative Ring Opening2.1 Three-Membered Rings: Ring Opening of Oxirane-2,3-dione2.2 Four-Membered Rings2.2.1 Ring Opening of Cyclobutanones2.2.2 Ring Opening of β-Lactams2.2.3 Ring Opening of β-Lactone2.3 Five-Membered Rings2.3.1 Ring Opening of Phthalimides2.3.2 Ring Opening of γ-Lactones2.3.3 Ring Opening of Anhydrides2.4 Six-Membered Rings2.5 Seven-Membered Rings3 Conclusion

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Identification of quinones as novel PIM1 kinase inhibitors

Cited by 12 publications

References 41 publications

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

Structure-Based Virtual Screening and De Novo Design of PIM1 Inhibitors with Anticancer Activity from Natural Products

Synthetically Important Ring-Opening Acylations of Alkoxybenzenes

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