Multiple myeloma: Combination therapy of BET proteolysis targeting chimeric molecule with CDK9 inhibitor

Lim, Su Lin; Xu, Liang; Han, Bangwoo; Pavithra, S.; Chng, Wee‐Joo; Koeffler, H. Phillip

doi:10.1371/journal.pone.0232068

Cited by 13 publications

(15 citation statements)

References 20 publications

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“…However, cyclin D1 overexpression may render the response to P276-00 therapy by making the MM cells more responsive to proliferative stimuli [ 34 ]. A synergistic effect of P276-00 and Doxorubicin was also reported in non-small cell lung carcinoma [ 42 ].…”

Section: Novel Cdk9 Inhibitors In Multiple Myelomamentioning

confidence: 82%

“…A higher apoptosis rate was observed in MM cell lines treated with both drugs in comparison to monotherapy. A synergistic effect has been shown in in-vivo MM xenograft models with no significant side effects, apart from minor weight loss (< 10%) [ 42 ]. AZD-4573 was able to cause apoptosis in T-cell lymphoma and AML xenograft models, showing the synergistic effect with Venetoclax [ 38 ].…”

Section: Novel Cdk9 Inhibitors In Multiple Myelomamentioning

confidence: 99%

“…AZD-4573 was able to cause apoptosis in T-cell lymphoma and AML xenograft models, showing the synergistic effect with Venetoclax [ 38 ]. According to Su-Lin Lim et al study AZD-4573 can inhibit the proliferation of multiple myeloma cell lines in-vitro, including Bortezomib- and Lenalidomide-resistant cell lines [ 42 ].…”

Section: Novel Cdk9 Inhibitors In Multiple Myelomamentioning

confidence: 99%

“…MC180295 inhibits the proliferation of numerous multiple myeloma cell lines. Even though MC180295 showed higher selectivity toward CDK9 than AZD-4573, it was not as potent [ 42 ]. MC180295 downregulated Myc and Mcl-1 in mantle cell lymphoma cell lines, as well as in Ibrutinib- and Venetoclax-resistant cell lines.…”

Section: Novel Cdk9 Inhibitors In Multiple Myelomamentioning

confidence: 99%

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CDK9 inhibitors in multiple myeloma: a review of progress and perspectives

et al. 2022

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Currently, multiple myeloma is not yet considered a curable disease. Despite the recent advances in therapy, the average patient lifespan is still unsatisfactory. Recently, CDK9 inhibitors emerged as a suitable agent to overcome resistance and prolong survival in patients with poor diagnoses. Downregulation of c-MYC, XIAP, Mcl-1 and restoration of p53 tumor-suppressive functions seems to play a key role in achieving clinical response. The applicability of the first generation of CDK9 inhibitors was limited due to relatively high toxicity, but the introduction of novel, highly selective drugs, seems to reduce the effects of off-target inhibition. CDK9 inhibitors were able to induce dose-dependent cytotoxicity in Doxorubicin-resistant, Lenalidomide-resistant and Bortezomib-resistant cell lines. They seem to be effective in cell lines with unfavorable prognostic factors, such as p53 deletion, t(4; 14) and t(14; 16). In preclinical trials, the application of CDK9 inhibitors led to tumor cells apoptosis, tumor growth inhibition and tumor mass reduction. Synergistic effects between CDK9 inhibitors and either Venetoclax, Bortezomib, Lenalidomide or Erlotinib have been proven and are awaiting verification in clinical trials. Although conclusions should be drawn with due care, obtained reports suggest that including CDK9 inhibitors into the current drug regimen may turn out to be beneficial, especially in poor prognosis patients.

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Section: Novel Cdk9 Inhibitors In Multiple Myelomamentioning

confidence: 82%

Section: Novel Cdk9 Inhibitors In Multiple Myelomamentioning

confidence: 99%

Section: Novel Cdk9 Inhibitors In Multiple Myelomamentioning

confidence: 99%

Section: Novel Cdk9 Inhibitors In Multiple Myelomamentioning

confidence: 99%

See 2 more Smart Citations

CDK9 inhibitors in multiple myeloma: a review of progress and perspectives

et al. 2022

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“…The protein bromodomain containing 4 (BRD4) binds to P-TEFb, a heterodimer of cyclin-dependent kinase 9 (CDK9) and cyclin T1 and promotes transcriptional elongation through phosphorylation of RNA polymerase II [ 210 , 211 ]. A PROTAC composed of pomalidomide linked to OTX-015, a small molecule that binds to BRD4 at the bromodomain and extra-terminal domain, induces BRD4 degradation and consequently decreases the activity of CDK9 and expression of its downstream target, MYC [ 212 ]. Thus, targeted protein degradation can be applied to develop novel inhibitors of protein–protein interactions [ 213 ].…”

Section: Future Directionsmentioning

confidence: 99%

Aurora A and AKT Kinase Signaling Associated with Primary Cilia

Nishimura

Yamakawa

Shiromizu

et al. 2021

Cells

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Dysregulation of kinase signaling is associated with various pathological conditions, including cancer, inflammation, and autoimmunity; consequently, the kinases involved have become major therapeutic targets. While kinase signaling pathways play crucial roles in multiple cellular processes, the precise manner in which their dysregulation contributes to disease is dependent on the context; for example, the cell/tissue type or subcellular localization of the kinase or substrate. Thus, context-selective targeting of dysregulated kinases may serve to increase the therapeutic specificity while reducing off-target adverse effects. Primary cilia are antenna-like structures that extend from the plasma membrane and function by detecting extracellular cues and transducing signals into the cell. Cilia formation and signaling are dynamically regulated through context-dependent mechanisms; as such, dysregulation of primary cilia contributes to disease in a variety of ways. Here, we review the involvement of primary cilia-associated signaling through aurora A and AKT kinases with respect to cancer, obesity, and other ciliopathies.

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