Response to Abemaciclib After 10 Lines of Therapy Including Palbociclib in Metastatic Breast Cancer: A Case Report With Literature Review

Wender, Isabella Osório; Haines, Kayla; Jahanzeb, Mohammad

doi:10.1007/s40487-020-00126-0

Cited by 4 publications

(2 citation statements)

References 18 publications

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“…It is an anti-cancerous agent that is reported to dually inhibit cyclin-dependent kinase 4 and 6 (CDK 4 and CDK 6). Abemaciclib is an FDA-approved drug used for the treatment of HR-positive and HER-negative metastatic breast cancer in combination with Fulvestrant [41]. Further, the drug has been used in various other trials including for the treatment of melanoma, lymphoma and solid tumors [42,43].…”

Section: Scaffold Analysismentioning

confidence: 99%

Identification of Novel Mutant (R132H) Isocitrate Dehydrogenase 1 Inhibitors for Glioma Therapy

Murali

Ramanathan

2022

J. Comput. Biophys. Chem.

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Neomorphic transformations in isocitrate dehydrogenase 1 (IDH1) are the key mutations prevalently found in various cancers including glioma. Recently identified mIDH1 specific inhibitors showed modest brain penetrating potential and dose-limiting toxicity. Herein, we elucidate virtual screening strategies to discover persuasive mIDH1 inhibitors from the approved subset of the DrugBank database consisting of 2715 molecules. Initially, a structural similarity search identified a total of 1432 lead molecules. The resultant compounds were inspected by molecular docking along with MM-GBSA and ADMET analyses. Altogether, the analyses identified Abemaciclib as the hit against mIDH1. Notably, abemaciclib was able to form hydrogen bond interaction with active site residues of mIDH1 protein. In the end, the dynamic behavior of the hit complex was also examined using molecular dynamics simulation studies. The outcome of the study culminates that the hit complex was stable throughout the simulation period of 100[Formula: see text]ns. It is worth noting that benzimidazole moiety of abemaciclib was reported to show inhibitory activity against glioma cells. Overall, these findings highlight that abemaciclib has the potential as a lead molecule against glioma. Indeed, the screened hit compound could be further explored for the development of mIDH1 inhibitor with great brain penetrating ability and low toxicity.

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Section: Scaffold Analysismentioning

confidence: 99%

Identification of Novel Mutant (R132H) Isocitrate Dehydrogenase 1 Inhibitors for Glioma Therapy

Murali

Ramanathan

2022

J. Comput. Biophys. Chem.

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“…Another case series published by Mariotti V. et al demonstrated a response with abemaciclib in some patients after progression on palbociclib with a median PFS of 7.0 months (range 1.8-12.1) [32]. Some other case reports and single-center experiences also suggest the clinical efficacy of abemaciclib in this setting [33][34][35].…”

Section: Discussionmentioning

confidence: 99%

Clinical Experience with Abemaciclib in Patients Previously Treated with Another CDK 4/6 Inhibitor in a Tertiary Hospital: A Case Series Study

de Luna Aguilar,

Fuentes,

Ortega Anselmi

et al. 2023

Cancers

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The three approved cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including abemaciclib, have shown differences in their preclinical, pharmacological, and clinical data. Abemaciclib stands out for its broader target range and more rapid and intense activity. It has demonstrated efficacy as a monotherapy or in combination with tamoxifen in endocrine-refractory metastatic breast cancer (MBC) patients with prior chemotherapy. However, the clinical data on abemaciclib after exposure to previous CDK4/6 inhibitors are limited. In this single-center retrospective case series, we identified all patients who received abemaciclib until February 2022 after experiencing documented progression on palbociclib or ribociclib. The safety profile and clinical outcomes of abemaciclib treatment in this specific patient cohort were evaluated. Eleven patients were included in this retrospective case series, nine receiving abemaciclib with tamoxifen. Eight patients had visceral involvement, and the median age was 69 (ranging from 42 to 84). The median time from the end of prior CDK4/6 inhibitor treatment to abemaciclib initiation was 17.5 months (ranging from 3 to 41 months). Patients had undergone a median of three prior therapies (ranging from 1 to 7), including chemotherapy in 54.5% of cases. The median follow-up time was six months (ranging from 1 to 22 months). The median progression-free survival (PFS) was 8 months (95% CI 3.9–12). Five patients continued abemaciclib treatment, and one patient with liver metastases achieved a complete hepatic response. The most common adverse events were diarrhea (72.7%, no grade ≥ 3) and asthenia (27.3%, no grade ≥ 3). Our preliminary findings suggest that abemaciclib could be an effective and safe treatment option for MBC patients who have previously received palbociclib or ribociclib.

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Identification of Novel Mutant (R132H) Isocitrate Dehydrogenase 1 Inhibitors for Glioma Therapy

Murali

Ramanathan

2022

Preprint

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Neomorphic transformation in isocitrate dehydrogenase 1 (IDH1) are the key mutations prevalently found in various cancers including glioma. Recently identified mIDH1 specific inhibitors such as ivosidenib and Vorasidenib were restricted for use due to its modest brain penetrating potential and dose limiting toxicity respectively. Herein, we elucidate integrated virtual screening strategies to discover persuasive mIDH1 inhibitors from the approved subset of the DrugBank database consisting of 2715 molecules. Initially, structural similarity search identified a total of 1432 lead molecules. The resultant compounds were inspected by molecular docking along with MM-GBSA and ADMET analyses. Altogether, the analyses identified DB12001 (Abemaciclib) as the hit against mIDH1. Notably, Abemaciclib was able to form hydrogen bond interaction with active site residues of mIDH1 protein. In the end, the dynamic behavior of the hit complex was also examined using molecular dynamic (MD) simulation studies. The outcome of the study culminates that the hit complex was stable throughout the simulation period of 100ns. It is worth noting that benzimidazole moiety of Abemaciclib was reported to show inhibitory activity against glioma cells. Overall, these findings highlight that DB12001 has the potential as lead molecule against glioma. Indeed the screened hit compound could be further explored for the development of mIDH1 inhibitor with great brain penetrating ability and low toxicity.

show abstract

Response to Abemaciclib After 10 Lines of Therapy Including Palbociclib in Metastatic Breast Cancer: A Case Report With Literature Review

Cited by 4 publications

References 18 publications

Identification of Novel Mutant (R132H) Isocitrate Dehydrogenase 1 Inhibitors for Glioma Therapy

Identification of Novel Mutant (R132H) Isocitrate Dehydrogenase 1 Inhibitors for Glioma Therapy

Clinical Experience with Abemaciclib in Patients Previously Treated with Another CDK 4/6 Inhibitor in a Tertiary Hospital: A Case Series Study

Identification of Novel Mutant (R132H) Isocitrate Dehydrogenase 1 Inhibitors for Glioma Therapy

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