A series of novel matrine aminophosphonate derivatives were designed and synthesized to explore more efficacious and less toxic Mcl-1 inhibitors, following the principle of combination and hybridization. The representative compound, 9 k, exhibited more potent cytotoxicity against human cervical cancer cells compared to the positive control 5-FU. A molecular docking study was also conducted to understand the interactions of 9 k with the Mcl-1 protein. Mechanistic studies revealed that compound 9 k could induce apoptosis in Hela cells, accompanied by changes in chromatin morphology, an elevation of intracellular ROS levels, and the dissipation of MMP. Notably, in vivo studies indicated that 9 k inhibited tumor growth in a Hela xenograft model. In summary, this study suggests that compound 9 k represents a potent and selective Mcl-1 inhibitor for the treatment of human cervical cancer.

08 Jan 2026·JOURNAL OF PHYSICAL CHEMISTRY B

Structure-Based Energetics of Human Bim Peptide Binding to Myeloid Cell Leukemia 1

Article

Author: Rajalakshmi, Vignesh Shanmugam ; Satpati, Priyadarshi

Mcl-1 is an antiapoptotic protein in the Bcl-2 family that is often overexpressed in cancer, making it a key therapeutic target. The Mcl-1 protein strongly binds (nM affinity) to the pro-apoptotic protein Bim and reduces the concentration of free Bim protein, facilitating the survival of cancer cells. Therefore, inhibiting Mcl-1 with small molecules by competing with and displacing the Bim protein offers significant potential for cancer treatment. The X-ray structure of human Mcl-1 in complex with the wild-type Bim peptide (BH3 domain of Bim protein) reveals that the peptide, in an amphipathic α-helical conformation, fits into the hydrophobic cleft of the Mcl-1 protein. We performed alchemical free energy simulations to quantitatively assess how amino acid mutations at 11 positions on the 23-residue peptide influence the stability of Mcl-1:Bim complex. A total of 54 mutant peptides, including aliphatic and nonstandard amino acid substitutions without altering the charge, were compared to the template Bim peptide. Mcl-1 incurs a large penalty of 3 kcal/mol for alanine mutations at residues (L10A and I13A), which are positioned in the middle of the peptide within its hydrophobic cleft of the protein. This penalty arises due to the loss of hydrophobic interactions. However, Mcl-1 showed weak discrimination (less than 1.5 kcal/mol) for other alanine mutations in the peptide, with the strength of discrimination decreasing for the residues near the terminals. These results support previous experimental observations showing a significant decrease in Mcl-1 affinity due to L10A and I13A mutations in Bim, with a lesser impact on affinity from other alanine mutations. Interestingly, the F17V mutation stabilizes the protein-peptide complex by 3 kcal/mol, indicating that the F17V-Bim mutant is a promising Mcl-1 inhibitor. Mcl-1 strongly disfavors the D15 → E15 mutation in the Bim peptide with a penalty of about 6.5 kcal/mol due to loss of salt bridge interactions. Notably, adding one carbon to the aliphatic arm in the Bim (D15 → E15) can significantly disrupt the electrostatic interactions. This highlights the necessity of achieving an optimal hydrophobic-hydrophilic balance for effective Mcl-1:peptide interactions. The study connects thermodynamics and structures to clarify the mechanism of peptide recognition by Mcl-1, providing valuable insights for designing Bim variants with enhanced affinity.

01 Dec 2025·Pharmacological Reports

MIM1 – a selective Mcl-1 protein inhibitor augments the proapoptotic activity of moxifloxacin toward MDA-MB-231 triple-negative breast cancer cells – a preliminary in vitro study

Article

Author: Beberok, Artur ; Wrześniok, Dorota ; Rok, Jakub ; Karkoszka-Stanowska, Marta ; Rzepka, Zuzanna

Abstract:

Background:

Triple-negative breast cancer (TNBC) is characterized by high invasiveness, high metastatic potential, and poor prognosis. TNBC is not sensitive to endocrine therapy or HER2-targeted treatment, highlighting the need for the development of standardized TNBC treatment regimens. Thus, the development of new TNBC treatment strategies has become an urgent need. MIM1 – BH3 mimetic, which inhibits Mcl-1 antiapoptotic protein, may be an efficacious molecule able to induce apoptosis. Previously, we found that moxifloxacin (MOXI) can modulate the Mcl-1 protein expression. Therefore, in the current study, we assessed the impact of MIM1 and MOXI/MIM1 mixtures on the viability and apoptosis in MDA-MB-231 breast cancer cells.

Methods:

The viability of cells was assessed by the WST-1 assay. The proapoptotic activity of the tested compounds was determined by cytometric technique.

Results:

The results showed that MIM1 exerted high cytotoxic and proapoptotic potential. In the case of two-component models, we have demonstrated that the use of MOXI and MIM1 mixtures resulted in a significant intensification of both cytotoxic and proapoptotic activity – shown as a modulatory effect on mitochondrial membrane potential, cell cycle distribution, or DNA fragmentation, toward MDA-MB-231 cells when compared with MIM1 or MOXI alone.

Conclusions:

We have reported, for the first time, the high proapoptotic activity of MIM1 toward MDA-MB-231 cells pointing to the Mcl-1 protein as an important molecular target. Moreover, the observed potential synergistic mode of action (expressed as a significant enhancement of the induction of apoptosis process) detected for MOXI and MIM1 in the two-component model may provide a new direction for further in vitro and in vivo experiments concerning the role of Mcl-1 protein in the treatment of TNBC.

Clinical trial number:

Not applicable.

News (Medical) associated with 483-LM

14 Aug 2025

·www.fiercebiotech.com

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.

Phase 1ADCPROTACs

21 Oct 2021

·www.biospace.com

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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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United States	The University of Michigan-Dearborn	-

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