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- | Journal: Design of rigid protein-protein interaction inhibitors enables targeting of undruggable Mcl-1. (Pubmed Central) - May 19, 2023
Despite being previously considered undruggable, seven small-molecule Mcl-1 inhibitors have recently entered clinical trials.
- | Journal, IO biomarker: NA1-115-7, from Zygogynum pancheri, is a new selective MCL-1 inhibitor inducing the apoptosis of hematological cancer cells but non-toxic to normal blood cells or cardiomyocytes. (Pubmed Central) - Aug 24, 2022
Synthetic inhibitors targeting these proteins have been developed, and some hematological malignancies are now widely treated with a BCL-2 inhibitor (venetoclax)...Six MCL-1 inhibitors (S64315, AZD-5991, AMG-176, AMG-397, ABBV-467 and PRT1419) have been evaluated in clinical trials since 2016, but some were affected by safety issues and none are currently used clinically...Importantly, a similar treatment with NA1-115-7 was not toxic to erythrocytes, peripheral blood mononuclear cells, platelets, or cardiomyocytes. These results highlight the potential of natural products for use as specific BH3 mimetics non-toxic to normal cells, and they suggest that NA1-115-7 may be a promising tool for use in cancer treatment.
- murizatoclax (AMG 397) / Amgen
Optimization and scale-up of a diastereoselective epoxide formation/nucleophilic ring-opening sequence to access a late stage intermediate of AMG 397 (W183b (McCormick Place Convention Center)) - Aug 9, 2022 - Abstract #ACSFall2022ACS_Fall_11516;
Additionally, a unique multi-phasic crystallization was developed, which facilitated the filtration/isolation processes by producing material with superior particle properties. These improved process conditions were successfully demonstrated on manufacturing scale.
- murizatoclax (AMG 397) / Amgen
Molecular Complexity as a Driver for Innovation in Pharmaceutical Process Development (Room 1B (San Diego Convention Center)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_6155;
The continued advance of novel synthetic methods and subsequent translation to efficient and scalable processes has enabled process chemists to overcome the challenges associated with this increasing complexity, and to deliver processes that meet the criteria for sustainability and green chemistry. The presentation will highlight case studies from the Amgen Process Chemistry laboratories.
- [VIRTUAL] Beyond BCL-2 Inhibition in Acute Myeloid Leukemia: Other Approaches to Leverage the Apoptotic Pathway () - Sep 6, 2021 - Abstract #SOHO2021SOHO_357;
While venetoclax heralded a paradigm shift for patients, we are now faced with challenges in patients who relapse or remain refractory. We have novel clinical stage compounds to methodologically target different facets of the apoptotic pathway and optimize novel combinations with the goal to improve the cure rates in AML patients.
- || Review, Journal, IO biomarker: Targeting MCL-1 in hematologic malignancies: Rationale and progress. (Pubmed Central) - May 20, 2021
Another important question is whether a safe therapeutic window can be found for this new class of inhibitors. In summary, inhibition of MCL-1 shows potential as a treatment for hematologic malignancies and clinical evaluation of MCL-1 inhibitors is currently underway.
- ||| murizatoclax (AMG 397) / Amgen
Trial termination: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - Mar 18, 2021
P1, N=24, Terminated, Sponsor: Amgen
In summary, inhibition of MCL-1 shows potential as a treatment for hematologic malignancies and clinical evaluation of MCL-1 inhibitors is currently underway. Active, not recruiting --> Terminated; Strategic decisions
- || murizatoclax (AMG 397) / Amgen
Enrollment closed, Enrollment change: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - Jan 19, 2021
P1, N=24, Active, not recruiting, Sponsor: Amgen
Active, not recruiting --> Terminated; Strategic decisions Recruiting --> Active, not recruiting | N=160 --> 24
- ||| murizatoclax (AMG 397) / Amgen
Enrollment open, Enrollment change, Trial completion date: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - Nov 13, 2020
P1, N=160, Recruiting, Sponsor: Amgen
Recruiting --> Active, not recruiting | N=160 --> 24 Active, not recruiting --> Recruiting | N=24 --> 160 | Trial completion date: Oct 2022 --> Feb 2024
- AMG 397 / Amgen
[VIRTUAL] Interdiction at a protein-protein interface: Discovery of AMG 397, a potent, selective and orally efficacious MCL-1 inhibitor (On Demand Oral) - Aug 20, 2020 - Abstract #ACSFall2020ACS-Fall_5546;
AMG 397 is also selective against other pro-survival BCL-2 family proteins and competitive for binding to MCL-1 with pro-apoptotic BCL-2 family members. This presentation will describe the discovery highlights and preclinical evaluation of AMG 397.
- |||| AMG 397 / Amgen
Amgen presents the preclinical profile of AMG-397, the 1st orally administered MCL-1 inhibitor in clinical development for hematologic malignancies. #ACSFall2020 (Twitter) - Aug 17, 2020
- AMG 397 / Amgen
[VIRTUAL] Discovery and preclinical evaluation of AMG 397, a potent, selective and orally bioavailable MCL1 inhibitor (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_2742;
AMG 397 was also tested in the MOLM-13 orthotopic model of AML where twice weekly administration at 10, 30 and 60 mg/kg achieved 47% tumor growth inhibition (TGI), 99% TGI and 75% regression respectively. Combination of AMG 397 at 10 mg/kg twice weekly and 50 mg/kg of venetoclax daily achieved 45% regression in the same model.
- | murizatoclax (AMG 397) / Amgen
Trial completion date, Trial primary completion date: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - Mar 20, 2020
P1, N=24, Active, not recruiting, Sponsor: Amgen
Combination of AMG 397 at 10 mg/kg twice weekly and 50 mg/kg of venetoclax daily achieved 45% regression in the same model. Trial completion date: Apr 2023 --> Oct 2022 | Trial primary completion date: Mar 2023 --> Oct 2022
- | murizatoclax (AMG 397) / Amgen
Trial completion date, Trial primary completion date: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - Oct 21, 2019
P1, N=24, Active, not recruiting, Sponsor: Amgen
Trial completion date: Apr 2023 --> Oct 2022 | Trial primary completion date: Mar 2023 --> Oct 2022 Trial completion date: Sep 2022 --> Apr 2023 | Trial primary completion date: Aug 2022 --> Mar 2023
- | murizatoclax (AMG 397) / Amgen
Trial completion date: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - Sep 25, 2019
P1, N=24, Active, not recruiting, Sponsor: Amgen
Trial completion date: Sep 2022 --> Apr 2023 | Trial primary completion date: Aug 2022 --> Mar 2023 Trial completion date: Aug 2023 --> Sep 2022
- | murizatoclax (AMG 397) / Amgen
Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - Aug 1, 2019
P1, N=24, Active, not recruiting, Sponsor: Amgen
Trial completion date: Aug 2023 --> Sep 2022 Recruiting --> Active, not recruiting | N=90 --> 24 | Trial completion date: Sep 2022 --> Aug 2023 | Trial primary completion date: Feb 2021 --> Aug 2022
- || murizatoclax (AMG 397) / Amgen
Trial completion date, Trial primary completion date: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - Jun 14, 2019
P1, N=90, Recruiting, Sponsor: Amgen
Recruiting --> Active, not recruiting | N=90 --> 24 | Trial completion date: Sep 2022 --> Aug 2023 | Trial primary completion date: Feb 2021 --> Aug 2022 Trial completion date: Feb 2022 --> Sep 2022 | Trial primary completion date: Aug 2020 --> Feb 2021
- || murizatoclax (AMG 397) / Amgen
Trial completion date, Trial primary completion date: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - Feb 26, 2019
P1, N=90, Recruiting, Sponsor: Amgen
Trial completion date: Feb 2022 --> Sep 2022 | Trial primary completion date: Aug 2020 --> Feb 2021 Trial completion date: Oct 2021 --> Feb 2022 | Trial primary completion date: May 2020 --> Aug 2020
- | murizatoclax (AMG 397) / Amgen
Trial completion date, Trial primary completion date: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - Nov 30, 2018
P1, N=90, Recruiting, Sponsor: Amgen
Trial completion date: Oct 2021 --> Feb 2022 | Trial primary completion date: May 2020 --> Aug 2020 Trial completion date: Dec 2020 --> Oct 2021 | Trial primary completion date: Dec 2020 --> May 2020
- || murizatoclax (AMG 397) / Amgen
Trial primary completion date: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - Sep 10, 2018
P1, N=90, Recruiting, Sponsor: Amgen
Trial completion date: Dec 2020 --> Oct 2021 | Trial primary completion date: Dec 2020 --> May 2020 Trial primary completion date: Feb 2020 --> Dec 2020
- ||| murizatoclax (AMG 397) / Amgen
Enrollment open, Trial primary completion date: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - Aug 14, 2018
P1, N=90, Recruiting, Sponsor: Amgen
Trial primary completion date: Feb 2020 --> Dec 2020 Not yet recruiting --> Recruiting | Trial primary completion date: Oct 2020 --> Feb 2020
- ||| murizatoclax (AMG 397) / Amgen
New P1 trial: Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies (clinicaltrials.gov) - Mar 13, 2018
P1, N=90, Not yet recruiting, Sponsor: Amgen