Targeting Mcl-1 is a promising antitumor strategy; however, no Mcl-1 inhibitors have been clinically approved, primarily due to their suboptimal drug-like properties and drug resistance rather than insufficient potency. Herein, we report the discovery of a novel tetrahydro-β-carboline (THBC)-derived Mcl-1 inhibitor, N5, which was identified by integrating structural insights with structure-based drug design (SBDD). N5 possesses a simple, synthetically accessible structure while exhibiting high binding affinity and selectivity for Mcl-1. This compound demonstrated potent cellular on-target activity, favorable ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, and in vivo efficacy in Mcl-1-dependent ovarian cancer xenograft models (A2780S). Notably, its hydrochloride (designated N5Y) exhibited even better antitumor efficacy as a single agent and the ability to overcome cisplatin resistance, producing significant synergistic effects in combination therapy. Collectively, N5 represents a promising lead compound for the development of clinically applicable Mcl-1 inhibitors, with the potential to address key challenges of efficacy, safety, and drug resistance.

2026-05-01·Indian Journal of Hematology and Blood Transfusion

Identification of Potential Biomarkers for Intervention of AMG-176 in the Chronic Lymphocytic Leukemia Based on Untargeted Metabolomic Analysis

Article

作者: Guan, Jun ; Yi, Xue ; Li, Qin ; Zhao, Zhigang ; Zhai, Yixin ; Xing, Donghui ; Wang, Lanlan

Supplementary Information:

The online version contains supplementary material available at 10.1007/s12288-025-02059-y.

2026-02-01·Molecular Oncology

Predictors of response and rational combinations for the novel MCL ‐1 inhibitor MIK665 in acute myeloid leukemia

Article

作者: Mika Kontro ; Ensar Halilovic ; Ezgi June Olgac ; Sofia Aakko ; Janghee Woo ; Joseph Saad ; Heiko Maacke ; Komal Kumar Javarappa ; Elmira Khabusheva ; Kimmo Porkka ; Nemo Ikonen ; Mahesh Tambe ; Alun Parsons ; Caroline A. Heckman ; Juho J. Miettinen ; Rhiannon Newman ; Heikki Kuusanmäki ; Eric Durand

Despite promising anti‐leukemic activity of MCL‐1 inhibitors in preclinical studies of acute myeloid leukemia (AML), clinical progress has been hindered by limited knowledge of target patient subgroups. To stratify patients for MCL‐1 inhibitor treatment, we evaluated the sensitivity of 42 primary AML samples to MCL‐1 inhibitor MIK665 (S64315) and analyzed their molecular profiles. We observed that MIK665‐sensitive samples had a more differentiated phenotype, whereas resistant samples displayed higher levels of ABCB1 (MDR1) and the anti‐apoptotic protein BCL‐XL. Moreover, ABCB1 expression had good predictive performance in identifying resistant samples. To induce sensitivity, we treated MIK665‐resistant samples with ABCB1 inhibitors elacridar or tariquidar, BCL‐XL inhibitor A1331852, or BCL‐2 inhibitor venetoclax in combination with MIK665. The combination of MIK665 with each of elacridar, tariquidar, or venetoclax effectively eliminated AML blasts compared to the agents alone, while the combination with A1331852 showed limited efficacy for this patient subgroup. Additionally, the combination of MIK665 with venetoclax restored sensitivity in samples with primary venetoclax resistance. Overall, this study indicates that elevated ABCB1 expression is a potentially targetable resistance mechanism in the context of MIK665 resistance, and that a combination of MIK665 with venetoclax may be effective for overcoming resistance to either MCL‐1 or BCL‐2 inhibition.

项与 483-LM 相关的新闻（医药）

2025-08-14

·FierceBiotech

Cancer biotech Prelude calls it curtains on lead SMARCA2 degrader

Prelude Therapeutics’ ditching of PRT3789 comes after the company had previously decided to go all-in on SMARCA2 degraders.\n Prelude Therapeutics’ lead asset won’t be making it to the second act. The precision oncology outfit is pausing development of SMARCA2 degrader PRT3789, leaving just one clinical program left humming in its pipeline.The decision comes after PRT3789 underwhelmed in a phase 1 dose escalation trial, Prelude said in an Aug. 14 release. The Delaware-based biotech will only take the asset forward with the help of a partner. The company’s internal resources will now focus solely on its other SMARCA2 degrader, PRT7732.“While PRT3789 demonstrated initial proof of concept for the mechanism, a number of considerations—including the potential need for higher target coverage throughout the dosing interval, and capital needs to continue to advance both agents—contributed to this decision,” CEO Kris Vaddi, Ph.D., said in the filing.PRT3789 and PRT7732 are designed to target the SMARCA2 protein, which cancer cells with a SMARCA4 mutation need to survive. The SMARCA4 mutation is linked to more aggressive forms of cancer, Prelude said in the release, and is found in 10% of all non-small cell lung cancers and 5% of all cancers in general. While PRT3789 is given intravenously, PRT7732 is given orally. Given “the clinical profile observed to date with PRT7732,” Vaddi said, Prelude will “explore the potential for this mechanism in SMARCA4 deleted cancers and determine the path forward for continued development by year-end.”Prelude’s ditching of PRT3789 comes after the company had previously decided to go all-in on SMARCA2 degraders. The company cut two phase 1 assets, an MCL-1 inhibitor and a CDK4/6 inhibitor, in November 2023 in order to make room for “top priority” PRT3789.First-in-human data from the now-solo PRT7732 is expected later this year, Prelude said in the release, and the company is also working on preclinical antibody-drug conjugates for SMARCA2 and SMARCA4 in tandem with AbCellera.Prelude’s stock seemed largely unaffected by the announcement of PRT3789’s curtain call, dipping slightly but then bouncing back to $0.96 per share by 10:35 a.m. ET, up from $0.91 at the prior day’s close.

临床1期抗体药物偶联物蛋白降解靶向嵌合体

2021-10-21

·BioSpace

AstraZeneca Cancer Trial Hit with Clinical Hold Following Cardiac Issues

Nathan Stirk/Getty Images A trial assessing an experimental AstraZeneca cancer drug has been placed on clinical hold due to safety concerns. The trial pause comes two years after Amgen was also forced to pause a study of a drug within the same class. AstraZeneca quietly announced the study on clinicaltrials.gov, but did not issue any formal statement regarding the pause. The company said the trial, which assesses AZD5991 in subjects with relapsed or refractory hematologic malignancies, was paused to allow “further evaluation of safety related information.” The pause was put into place on Oct. 19, according to the site. AZD5991 is a direct inhibitor of Mcl-1, a difficult target for oncology drugs and a well-known drug-resistance driver. AstraZeneca’s experimental drug is designed to target apoptosis, which is the process of programmed cell death in hematological cancer. AstraZeneca was assessing AZD5991 in combination with Roche’s venetoclax in patients with relapsed or refractory acute myeloid leukemia (AML), as well as a monotherapy treatment. Venetoclax, co-developed by Roche and AbbVie, is a small molecule inhibitor of the BCL-2 protein. According to multiple outlets, the trial was placed on clinical hold following signs of heart issues in one patient who received the combination treatment. In a statement sent to Fierce Biotech, the first outlet to report on the hold, the company noted “asymptomatic elevation in cardiovascular laboratory parameters.” According to the report, this occurred in an AML patient who had additional comorbidities. AstraZeneca noted there were no safety signs in individuals who received AZD5991 as a monotherapy. “It is important to note that the asymptomatic elevation has since resolved. We are now in the process of conducting a full analysis of the study data and working closely with the FDA for the benefit of the patients,” an AstraZeneca spokesperson said according to the report. The study was designed to be a three-part, open-label, non-randomized trial designed to test the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of ascending doses of AZD5991 alone or in combination with venetoclax in patients with relapsed or refractory hematologic malignancies. The safety concern noted in the AstraZeneca study is similar to what Amgen faced two years ago when its study was placed on clinical hold. Earlier this year, California-based Amgen opted to scrap its study of AMG 397, an oral MCL-1 inhibitor. As BioSpace previously reported, the Amgen study was terminated to shift focus to studies of AMG 176, an intravenously dosed inhibitor of MCL-1. That asset is currently being assessed in a Phase I study for hematological malignancies.

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