Novel compounds with potent CDK9 inhibitory activity for the treatment of myeloma

Czudor, Zsófia; Balogh, M.; Bánhegyi, Péter; Boros, Sándor; Breza, Nóra; Dobos, Judit; Fábian, Martin; Horváth, Zoltán; Illyés, Eszter; Möller, Peter; Sipos, Andrea; Szántai-Kis, Csaba; Szokol, Bálint; Őrfi, László

doi:10.1016/j.bmcl.2018.01.002

Cited by 20 publications

(14 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed that patients with a high expression of CDK9 have significantly worse outcomes in terms of OS and PFS. This significant correlation between CDK9 expression and patient outcome is consistent with previous works on other cancers and adds to a growing body of evidence recognizing CDK9 as a potential prognostic marker 13, 25, 26. For example, CDK9 can be highly expressed in pancreatic cancers, and when elevated, correlates to worse outcomes for these patients 13.…”

Section: Discussionsupporting

confidence: 88%

Aberrant CDK9 expression within chordoma tissues and the therapeutic potential of a selective CDK9 inhibitor LDC000067

Shen¹,

Dean²,

Yu³

et al. 2020

J. Cancer

View full text Add to dashboard Cite

Objectives: Chordomas are slow-growing malignancies that commonly affect vital neurological structures. These neoplasms are highly resistant to current chemotherapeutic regimens and often recur after surgical intervention. Therefore, there is an urgent need to identify molecular targets and more robust drugs to improve chordoma patient outcomes. It is well accepted that cyclin-dependent protein kinase 9 (CDK9) has tumorigenic roles in various cancers; however, the expression and significance of CDK9 in chordoma remains unknown. Methods: Expression of CDK9 in chordoma cell lines and tumor tissues was examined by Western blot and immunohistochemistry (IHC). The correlation between CDK9 expression in patient tissues and clinical prognosis was analyzed. The functional roles of CDK9 in chordoma were investigated after the addition of small interfering RNA (siRNA) and CDK9 inhibitor (LDC000067). Cell growth and proliferation were assessed with MTT and clonogenic assays. The effect of CDK9 inhibition on chordoma cells was further evaluated with a three-dimensional (3D) cell culture model which mimics the in vivo environment. Results: CDK9 was expressed in both chordoma cell lines and chordoma tissues. High-expression of CDK9 correlated with recurrence and poor outcomes for chordoma patients. CDK9 silencing with siRNA decreased growth and proliferation of chordoma cells and lowered levels of Mcl-1 and RNA polymerase II (RNAP II) phosphorylation. Pharmacological inhibition of CDK9 with the small molecular inhibitor LDC000067 reduced cell growth, supported apoptosis, suppressed cell colony formation in a clonogenic assay, and decreased spheroid growth in 3D culture. Conclusion: We demonstrate that CDK9 expression in chordoma correlates with patient outcome, and, when inhibited, chordoma cell growth and proliferation significantly decreases. Taken together, these results support CDK9 as an emerging potential target in chordoma therapy.

show abstract

Section: Discussionsupporting

confidence: 88%

Aberrant CDK9 expression within chordoma tissues and the therapeutic potential of a selective CDK9 inhibitor LDC000067

Shen¹,

Dean²,

Yu³

et al. 2020

J. Cancer

View full text Add to dashboard Cite

show abstract

“…All models we created were based on a set of 41 CDK9 inhibitors that was synthesized by our research group [17]. We kept the numbering of the compounds as it is in the abovementioned paper.…”

Section: Data Setmentioning

confidence: 99%

“…As for ionization forms, we generated the most possible state of each molecule with Ionizer at target pH of 7.4. The negative logarithm values (pIC 50 ) of the previously published inhibitory activities were calculated and used for the model building [17]. Flexible Ligand Alignment procedure of the Maestro GUI was utilized for the superposition of the ligands.…”

Section: Protein and Ligand Preparationmentioning

confidence: 99%

New computational studies to support cyclin-dependent kinase 9 inhibitor screening and design

Fábian

Balogh

Czudor

et al. 2019

APH

Self Cite

View full text Add to dashboard Cite

Aims: Cyclin-dependent kinase 9 (CDK9) plays a major role in the regulation of transcription. Its overexpression -which occurs in several types of cancer- increases the levels of certain antiapoptotic proteins that can lead to tumorigenesis, therefore the identification of new, more potent and more selective inhibitors is essential. Methods: In this study we present a computational approach, which can facilitate lead selection and optimization. Results: First, a pharmacophore hypothesis based on the active compounds has been developed to identify the key features for the ligand-target interaction. This was followed by the docking of the compounds into the active site of CDK9, the poses and interactions with the amino acids were compared with those of the co-crystallized ligand. The mode of their binding further explained the characteristics of these inhibitors while the docking scores can be a factor in the selection of active compounds in the future. Finally, a field-based QSAR model was also created, to predict the activity of inhibitor candidates. Conclusion: With our current work we deepened our knowledge about the interactions between CDK9 and its inhibitors, which can contribute to the discovery of novel CDK9 inhibitors.

show abstract

“…[53,54] antifungal, [55,56] antiviral, [57][58][59] antibacterial, [60] antimalarial, [61] anti-HIV, [62,63] antiulcer, [64] insecticide, [65] antineoplastic, [66] antiepileptic, [67] analgesic, [68] and anthelmintic. [69] Several commercially available drugs derived from pyrimidine are sildenafil (viagra), formycin A, [70] sulfadiazine, [71] pyrimethamine, [72] roscovitine, [73] indiplon, zaleplon, [74] ocinaplon, [75] dinaciclib, [75] fluorastrol, [76] 5-fluorouracil, [77] ispinesib, [78] volasertib, [79] pictilisib, monastrol, [80] and etravirine [81] (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

One‐potandtwo‐potmethods for chalcone derived pyrimidines synthesis and applications

Farooq

Ngaini

2021

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

Chalcone-derived pyrimidine is a well-known heterocyclic compound that is commonly present in ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) bio-isosteres. Pyrimidine derivatives are effective in both the electronic industry and drug industries. This review highlights the synthesis of pyrimidines, namely mono-pyrimidine, bis-pyrimidine, fused pyrimidine, symmetric, and asymmetric pyrimidine via one-pot and two-pot methods. The one-pot method is the direct reaction of amino derivatives with aldehydes and acetophenones, whereas the two-pot method is frequently reported for the synthesis of chalcone before the cyclization to a pyrimidine. This review is important in organic synthesis, particularly in the heterocyclic field, regarding pyrimidines and their significance in therapeutic and electronic industries.

show abstract

Novel compounds with potent CDK9 inhibitory activity for the treatment of myeloma

Cited by 20 publications

References 26 publications

Aberrant CDK9 expression within chordoma tissues and the therapeutic potential of a selective CDK9 inhibitor LDC000067

Aberrant CDK9 expression within chordoma tissues and the therapeutic potential of a selective CDK9 inhibitor LDC000067

New computational studies to support cyclin-dependent kinase 9 inhibitor screening and design

One‐potandtwo‐potmethods for chalcone derived pyrimidines synthesis and applications

Contact Info

Product

Resources

About