Biphenylsulfonamides as effective MMP-2 inhibitors with promising antileukemic efficacy: Synthesis, in vitro biological evaluation, molecular docking, and MD simulation analysis.

Overexpression of matrix metalloproteinase-2 (MMP-2) possesses a correlation with leukemia especially chronic myeloid leukemia (CML). However, no such MMP-2 inhibitor has come out in the market to date for treating leukemia. In this study, synthesis, biological evaluation, and molecular modeling studies of a set of biphenylsulfonamide derivatives as promising MMP-2 inhibitors were performed, focusing on their potential applications as antileukemic therapeutics. Compounds DH-18 and DH-19 exerted the most effective MMP-2 inhibition (IC50 of 139.45 nM and 115.16 nM, respectively) with potent antileukemic efficacy against the CML cell line K562 (IC50 of 0.338 µM and 0.398 µM, respectively). The lead molecules DH-18 and DH-19 reduced the MMP-2 expression by 21.3% and 17.8%, respectively with effective apoptotic induction (45.4% and 39.8%, respectively) in the K562 cell line. Moreover, both these compounds significantly arrested different phases of the cell cycle. Again, both these molecules depicted promising antiangiogenic efficacy in the ACHN cell line. Nevertheless, the molecular docking and molecular dynamics (MD) simulation studies revealed that DH-18 formed strong bidentate chelation with the catalytic Zn2+ ion through the hydroxamate zinc binding group (ZBG). Apart from that, the MD simulation study also disclosed stable binding interactions of DH-18 and MMP-2 along with crucial interactions with active site amino acid residues namely His120, Glu121, His124, His130, Pro140, and Tyr142. In a nutshell, this study highlighted the importance of biphenylsulfonamide-based novel and promising MMP-2 inhibitors to open up a new avenue for potential therapy against CML.

Long-term hybrid stability and matrix metalloproteinase inhibition by fucosterol in resin-dentin bonding biomechanics.

Fucosterols have been widely studied for their antioxidant, anticancer, and anti-inflammatory properties. However, they have not yet been studied in the field of dentistry. This study aimed to determine whether pretreatment of dentin with fucosterol before resin restoration enhances bond stability in resin-dentin hybrid layers. After applying 0.1, 0.5, and 1.0 wt% fucosterol to demineralized dentin, microtensile bond strength (MTBS) and nanoleakage tests were performed before and after collagenase aging, and the surface was observed using scanning electron microscope (SEM). The fucosterol-treated group showed better bond strength and less nanoleakage both before and after collagenase aging, and the corresponding structures were confirmed using SEM. MMP zymography confirmed that the activity of MMPs was relatively low along the concentration gradient of fucosterol, and the FTIR analysis confirmed the production of collagen crosslinks. In addition, fucosterol exhibits cytotoxicity against Streptococcus mutans, the main cause of dental decay. The results of this study suggest that fucosterol pretreatment improves bond strength and reduces nanoleakage at the resin-dentin interface, possibly through a mechanism involving collagen cross-link formation via the inhibition of endogenous and exogenous MMP activity. This study demonstrates the potential of fucosterol as an MMP inhibitor in dentin, which contributes to long-term resin-dentin bond stability and can be used as a restorative material.

Non-small cell lung cancer sensitisation to platinum chemotherapy via new thiazole-triazole hybrids acting as dual T-type CCB/MMP-9 inhibitors.

Cisplatin remains the unchallenged standard therapy for NSCLC. However, it is not completely curative due to drug resistance and oxidative stress-induced toxicity. Drug resistance is linked to overexpression of matrix metalloproteinases (MMPs) and aberrant calcium signalling. We report synthesis of novel thiazole-triazole hybrids as MMP-9 inhibitors with T-type calcium channel blocking and antioxidant effects to sensitise NSCLC to cisplatin and ameliorate its toxicity. MTT and whole cell patch clamp assays revealed that 6d has a balanced profile of cytotoxicity (IC50 = 21 ± 1 nM, SI = 12.14) and T-type calcium channel blocking activity (⁓60% at 10 µM). It exhibited moderate ROS scavenging activity and nanomolar MMP-9 inhibition (IC50 = 90 ± 7 nM) surpassing NNGH with MMP-9 over -2 and MMP-10 over -13 selectivity. Docking and MDs simulated its receptor binding mode. Combination studies confirmed that 6d synergized with cisplatin (CI = 0.69 ± 0.05) lowering its IC50 by 6.89 folds. Overall, the study introduces potential lead adjuvants for NSCLC platinum-based therapy.

Polygalacturonic acid partially inhibits matrix metalloproteinases and dehydration in wounds.

BACKGROUND: Key wound environment parameters include pH, hydration, and the balance between tissue remodeling and deposition of new tissue. When prolonged inflammation is present, the proliferation phase of wound healing can be delayed because excessive protease production due to persistent inflammation can destroy newly formed tissue and prevent wounds from filling and reepithelializing. OBJECTIVE: To conduct an in vitro study of the ability of polygalacturonic acid (PG), a natural pectin derivative present in ripening fruit, to inhibit 3 destructive wound proteases and prevent dehydration in environments in which significant evaporation can occur. MATERIALS AND METHODS: In vitro enzyme inhibition assay kits were used to detect the ability of PG to inhibit key wound proteases matrix metalloproteinase (MMP)-2, MMP-9, and neutrophil elastase (NE). Transepidermal evaporative water loss from a polyvinyl alcohol skin substitute hydrogel was gravimetrically measured. RESULTS: PG could partially inhibit MMP-2 (>50% inhibition relative to negative controls), MMP-9 (>50% inhibition relative to negative controls), and NE (>25% inhibition relative to negative controls) and thereby potentially blunt some of the destructive effects of excess proteases where prolonged inflammation is present. In an in vitro transepidermal evaporative water loss assay, PG also helped retain moisture and inhibited dehydration (>25% reduction relative to negative controls). CONCLUSIONS: These findings suggest that PG can be a useful addition to ointments and dressings in wound care and warrants further in vivo testing.

Matrix metalloproteinases in aortic dissection.

Aortic dissection, characterized by a high immediate mortality, is primarily caused by excessive bleeding within the walls of the aorta or a severe tear within the intimal layer of the aorta. Inflammation, as well as oxidative stress and the degradation of extracellular matrix (ECM), are significant factors in the development and occurrence of aortic dissection. Matrix metalloproteinases (MMPs) are pivotal enzymes responsible for degrading the ECM. Inflammatory factors and oxidants can interact with MMPs, indicating the potential significance of MMPs in aortic dissection. A substantial body of evidence indicates that numerous MMPs are significantly upregulated in aortic dissection, playing a critical role in ECM degradation and the pathogenesis of aortic dissection. Furthermore, targeting these enzymes has demonstrated potential in facilitating ECM restoration and reducing the incidence of aortic dissection. This review initially provides a brief overview of MMP biology before delving into their expression patterns, regulatory mechanisms, and therapeutic applications in aortic dissection. A profound comprehension of the catabolic pathways associated with aortic dissection is imperative for the future development of potential preventive or therapeutic bio-interventions for aortic dissection.

Pinpointing prime structural attributes of potential MMP-2 inhibitors comprising alkyl/arylsulfonyl pyrrolidine scaffold: a ligand-based molecular modelling approach validated by molecular dynamics simulation analysis.

MMP-2 overexpression is strongly related to several diseases including cancer. However, none of the MMP-2 inhibitors have been marketed as drug candidates due to various adverse effects. Here, a set of sulphonyl pyrrolidines was subjected to validation of molecular modelling followed by binding mode analysis to explore the crucial structural features required for the discovery of promising MMP-2 inhibitors. This study revealed the importance of hydroxamate as a potential zinc-binding group compared to the esters. Importantly, hydrophobic and sterical substituents were found favourable at the terminal aryl moiety attached to the sulphonyl group. The binding interaction study revealed that the S1' pocket of MMP-2 similar to 'a basketball passing through a hoop' allows the aryl moiety for proper fitting and interaction at the active site to execute potential MMP-2 inhibition. Again, the sulphonyl pyrrolidine moiety can be a good fragment necessary for MMP-2 inhibition. Moreover, some novel MMP-2 inhibitors were also reported. They showed the significance of the 3rd position substitution of the pyrrolidine ring to produce interaction inside S2' pocket. The current study can assist in the design and development of potential MMP-2 inhibitors as effective drug candidates for the management of several diseases including cancers in the future.

Breaking the Cycle: Matrix Metalloproteinase Inhibitors as an Alternative Approach in Managing Tuberculosis Pathogenesis and Progression.

Mycobacterium tuberculosis (Mtb) has long posed a significant challenge to global public health, resulting in approximately 1.6 million deaths annually. Pulmonary tuberculosis (TB) instigated by Mtb is characterized by extensive lung tissue damage, leading to lesions and dissemination within the tissue matrix. Matrix metalloproteinases (MMPs) exhibit endopeptidase activity, contributing to inflammatory tissue damage and, consequently, morbidity and mortality in TB patients. MMP activities in TB are intricately regulated by various components, including cytokines, chemokines, cell receptors, and growth factors, through intracellular signaling pathways. Primarily, Mtb-infected macrophages induce MMP expression, disrupting the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thereby impairing extracellular matrix (ECM) deposition in the lungs. Recent research underscores the significance of immunomodulatory factors in MMP secretion and granuloma formation during Mtb pathogenesis. Several studies have investigated both the activation and inhibition of MMPs using endogenous MMP inhibitors (i.e., TIMPs) and synthetic inhibitors. However, despite their promising pharmacological potential, few MMP inhibitors have been explored for TB treatment as host-directed therapy. Scientists are exploring novel strategies to enhance TB therapeutic regimens by suppressing MMP activity to mitigate Mtb-associated matrix destruction and reduce TB induced lung inflammation. These strategies include the use of MMP inhibitor molecules alone or in combination with anti-TB drugs. Additionally, there is growing interest in developing novel formulations containing MMP inhibitors or MMP-responsive drug delivery systems to suppress MMPs and release drugs at specific target sites. This review summarizes MMPs' expression and regulation in TB, their role in immune response, and the potential of MMP inhibitors as effective therapeutic targets to alleviate TB immunopathology.

Unveiling the bidirectional role of MMP9: A key player in kidney injury.

Matrix metalloproteinases (MMPs) are a group of zinc-dependent proteolytic metalloenzymes that are involved in numerous pathological conditions, including nephropathy. MMP9, a member of the MMPs family, is categorized as a constituent of the gelatinase B subgroup, and its involvement in extracellular matrix (ECM) remodeling and renal fibrosis highlights its importance in the development and progression of renal diseases. The exact role of MMP9 in the development of kidney diseases is still controversial. This study investigated the dual role of MMP9 in kidney injury, discussing its implications in the pathogenesis of kidney diseases and investigating the design and mechanism of MMP9 inhibitors based on previous studies. This study provides an effective basis for the development of novel and selective MMP9 inhibitors for treating renal diseases.

Skin Malignant Melanoma and Matrix Metalloproteinases: Promising Links to Efficient Therapies.

Skin malignant melanoma (MM) is one of the most frequent and aggressive neoplasia worldwide. Its associated high mortality rates are mostly due to its metastases, while diagnosis and treatment of MM in its early stages is of favorable prognostic. Even skin superficial MMs at incipient local stages can already present with lymph node invasion and distant metastases. Therefore, knowledge of the controllable risk factors and pathogenic mechanisms of MM development, spreading, and metastatic pattern, as well as early diagnosis, are essential to decrease the high mortality rates associated with cutaneous malignant melanoma. Genetic factors are incriminated, although lifetime-acquired genetic mutations appear to be even more frequently involved in the development of MM. Skin melanocytes divide only twice per year and have time to accumulate genetic mutations as a consequence of environmental aggressive factors, such as UV exposure. In the search for more promising therapies, matrix metalloproteinases have become of significant interest, such as MMP-1, MMP-2, MMP-9, and MMP-13, which have been linked to more aggressive forms of cancer and earlier metastases. Therefore, the development of specific synthetic inhibitors of MMP secretion or activity could represent a more promising and effective approach to the personalized treatment of MM patients.

Inhibition mechanism of theaflavins on matrix metalloproteinase-2: inhibition kinetics, multispectral analysis, molecular docking and molecular dynamics simulation.

Dental caries is a chronic and destructive disease and matrix metalloproteinase-2 (MMP-2) plays a major role in caries. The inhibitory mechanisms of theaflavins [theaflavin (TF1), theaflavin-3-gallate (TF2A), theaflavin-3'-gallate (TF2B), and theaflavin-3,3'-digallate (TF3)] on MMP-2 were investigated using techniques such as enzyme inhibition kinetics, multi-spectral methods, molecular docking, and molecular dynamics simulations. The results showed that TF1, TF2A, TF2B, and TF3 all competitively and reversibly inhibited MMP-2 activity. Fluorescence spectra and molecular docking indicated that four theaflavins spontaneously bind to MMP-2 through noncovalent interactions, driven by hydrogen bonds and hydrophobic interactions, constituting a static quenching mechanism and resulting in an altered tryptophan residue environment around MMP-2. Molecular dynamic simulations demonstrated that four theaflavins can form stable, compact complexes with MMP-2. In addition, the order of theaflavins' ability to inhibit MMP-2 was found to be TF1 > TF2B > TF2A > TF3. Interestingly, the order of binding capacity between MMP-2 and TF1, TF2A, TF2B, and TF3 was consistent with the order of inhibitory capacity, and was opposite to the order of steric hindrance of theaflavins. This may be due to the narrow space of the active pocket of MMP-2, and the smaller the steric hindrance of theaflavins, the easier it is to enter the active pocket and bind to MMP-2. This study provided novel insights into theaflavins as functional components in the exploration of natural MMP-2 inhibitors.

MMPs as potential molecular targets in epithelial-to-mesenchymal transition driven COPD progression.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality globally and the risk of developing lung cancer is six times greater in individuals with COPD who smoke compared to those who do not smoke. Matrix metalloproteinases (MMPs) play a crucial role in the pathophysiology of respiratory diseases by promoting inflammation and tissue degradation. Furthermore, MMPs are involved in key processes like epithelial-to-mesenchymal transition (EMT), metastasis, and invasion in lung cancer. While EMT has traditionally been associated with the progression of lung cancer, recent research highlights its active involvement in individuals with COPD. Current evidence underscores its role in orchestrating airway remodeling, fostering airway fibrosis, and contributing to the potential for malignant transformation in the complex pathophysiology of COPD. The precise regulatory roles of diverse MMPs in steering EMT during COPD progression needs to be elucidated. Additionally, the less-understood aspect involves how these MMPs bi-directionally activate or regulate various EMT-associated signaling cascades during COPD progression. This review article explores recent advancements in understanding MMPs' role in EMT during COPD progression and various pharmacological approaches to target MMPs. It also delves into the limitations of current MMP inhibitors and explores novel, advanced strategies for inhibiting MMPs, potentially offering new avenues for treating respiratory diseases.

A Novel Strategy for the Treatment of Aneurysms: Inhibition of MMP-9 Activity through the Delivery of TIMP-1 Encoding Synthetic mRNA into Arteries.

Aneurysms pose life-threatening risks due to the dilatation of the arteries and carry a high risk of rupture. Despite continuous research efforts, there are still no satisfactory or clinically effective pharmaceutical treatments for this condition. Accelerated inflammatory processes during aneurysm development lead to increased levels of matrix metalloproteinases (MMPs) and destabilization of the vessel wall through the degradation of the structural components of the extracellular matrix (ECM), mainly collagen and elastin. Tissue inhibitors of metalloproteinases (TIMPs) directly regulate MMP activity and consequently inhibit ECM proteolysis. In this work, the synthesis of TIMP-1 protein was increased by the exogenous delivery of synthetic TIMP-1 encoding mRNA into aortic vessel tissue in an attempt to inhibit MMP-9. In vitro, TIMP-1 mRNA transfection resulted in significantly increased TIMP-1 protein expression in various cells. The functionality of the expressed protein was evaluated in an appropriate ex vivo aortic vessel model. Decreased MMP-9 activity was detected using in situ zymography 24 h and 48 h post microinjection of 5 µg TIMP-1 mRNA into the aortic vessel wall. These results suggest that TIMP-1 mRNA administration is a promising approach for the treatment of aneurysms.

Derivatives of D(-) glutamine-based MMP-2 inhibitors as an effective remedy for the management of chronic myeloid leukemia-Part-I: Synthesis, biological screening and in silico binding interaction analysis.

Chronic myeloid leukemia (CML) is a global issue and the available drugs such as tyrosine kinase inhibitors (TKIs) comprise various toxic effects as well as resistance and cross-resistance. Therefore, novel molecules targeting specific enzymes may unravel a new direction in antileukemic drug discovery. In this context, targeting gelatinases (MMP-2 and MMP-9) can be an alternative option for the development of novel molecules effective against CML. In this article, some D(-)glutamine derivatives were synthesized and evaluated through cell-based antileukemic assays and tested against gelatinases. The lead compounds, i.e., benzyl analogs exerted the most promising antileukemic potential showing nontoxicity in normal cell line including efficacious gelatinase inhibition. Both these lead molecules yielded effective apoptosis and displayed marked reductions in MMP-2 expression in the K562 cell line. Not only that, but both of them also revealed effective antiangiogenic efficacy. Importantly, the most potent MMP-2 inhibitor, i.e., benzyl derivative of p-tosyl D(-)glutamine disclosed stable binding interaction at the MMP-2 active site correlating with the highly effective MMP-2 inhibitory activity. Therefore, such D(-)glutamine derivatives might be explored further as promising MMP-2 inhibitors with efficacious antileukemic profiles for the treatment of CML in the future.

Pharmacological Inhibition of MMP-12 Exerts Protective Effects on Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice.

Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation and elastin degradation, in conjunction with superimposed atherosclerosis. Previous genetic ablation studies have proposed contradictory roles for MMP-12 in AAA development. In this study, we aimed to elucidate if pharmacological inhibition of MMP-12 activity with a phosphinic peptide inhibitor protects from AAA formation and progression in angiotensin (Ang) II-infused Apoe-/- mice. Complimentary studies were conducted in a human ex vivo model of early aneurysm development. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Apoe-/- mice from Ang II-induced AAA formation and rupture-related death, associated with diminished medial thinning and elastin fragmentation alongside increased collagen deposition. Proteomic analyses confirmed a beneficial effect of MMP-12 inhibition on extracellular matrix remodeling proteins combined with inflammatory pathways. Furthermore, RXP470.1 treatment of mice with pre-existing AAAs exerted beneficial effects as observed through suppressed aortic dilation and rupture, medial thinning, and elastin destruction. Our findings indicate that pharmacological inhibition of MMP-12 activity retards AAA progression and improves survival in mice providing proof-of-concept evidence to motivate translational work for MMP-12 inhibitor therapy in humans.

Doxycycline protects against sepsis-induced endothelial glycocalyx shedding.

Endothelial glycocalyx (eGC) covers the inner surface of the vessels and plays a role in vascular homeostasis. Syndecan is considered the "backbone" of this structure. Several studies have shown eGC shedding in sepsis and its involvement in organ dysfunction. Matrix metalloproteinases (MMP) contribute to eGC shedding through their ability for syndecan-1 cleavage. This study aimed to investigate if doxycycline, a potent MMP inhibitor, could protect against eGC shedding in lipopolysaccharide (LPS)-induced sepsis and if it could interrupt the vascular hyperpermeability, neutrophil transmigration, and microvascular impairment. Rats that received pretreatment with doxycycline before LPS displayed ultrastructural preservation of the eGC observed using transmission electronic microscopy of the lung and heart. In addition, these animals exhibited lower serum syndecan-1 levels, a biomarker of eGC injury, and lower perfused boundary region (PBR) in the mesenteric video capillaroscopy, which is inversely related to the eGC thickness compared with rats that only received LPS. Furthermore, this study revealed that doxycycline decreased sepsis-related vascular hyperpermeability in the lung and heart, reduced neutrophil transmigration in the peritoneal lavage and inside the lungs, and improved some microvascular parameters. These findings suggest that doxycycline protects against LPS-induced eGC shedding, and it could reduce vascular hyperpermeability, neutrophils transmigration, and microvascular impairment.

Matrix metalloproteinases targeting in prostate cancer.

Prostate cancer (PCa) is one of the most common tumors affecting men all over the world. PCa has brought a huge health burden to men around the world, especially for elderly men, but its pathogenesis is unclear. In prostate cancer, epigenetic inheritance plays an important role in the development, progression, and metastasis of the disease. An important role in cancer invasion and metastasis is played by matrix metalloproteinases (MMPs), zinc-dependent proteases that break down extracellular matrix. We review two important forms of epigenetic modification and the role of matrix metalloproteinases in tumor regulation, both of which may be of significant value as novel biomarkers for early diagnosis and prognosis monitoring. The author considers that both mechanisms have promising therapeutic applications for therapeutic agent research in prostate cancer, but that efforts should be made to mitigate or eliminate the side effects of drug therapy in order to maximize quality of life of patients. The understanding of epigenetic modification, MMPs, and their inhibitors in the functional regulation of prostate cancer is gradually advancing, it will provide a new technical means for the prevention of prostate cancer, early diagnosis, androgen-independent prostate cancer treatment, and drug research.

On-demand release of a selective MMP-13 blocker from an enzyme-responsive injectable hydrogel protects cartilage from degenerative progression in osteoarthritis.

In osteoarthritis (OA), the degradation of cartilage is primarily driven by matrix metalloprotease-13 (MMP-13). Hence, the inhibition of MMP-13 has emerged as an attractive target for OA treatment. Among the various approaches that are being explored for MMP-13 regulation, blocking of the enzyme with specific binding molecules appears to be a more promising strategy for preventing cartilage degeneration. To enhance effectiveness and ensure patient compliance, it is preferable for the binding molecule to exhibit sustained activity when administered directly into the joint. Herein, we present an enzyme-responsive hydrogel that was designed to exhibit on-demand, the sustained release of BI-4394, a potent and highly selective MMP-13 blocker. The stable and compatible hydrogel was prepared using triglycerol monostearate. The efficacy of the hydrogel to prevent cartilage damage was assessed in a rat model of OA induced by anterior cruciate ligament transection (ACLT). The results revealed that in comparison to the rats administrated weekly with intra-articular BI-4394, the hydrogel implanted rats had reduced levels of inflammation and bone erosion. In comparison to untreated control, the cartilage in animals administered with BI-4394/hydrogel exhibited significant levels of collagen-2 and aggrecan along with reduced MMP-13. Overall, this study confirmed the potential of BI-4394 delivery using an enzyme-responsive hydrogel as a promising treatment option to treat the early stages of OA by preventing further cartilage degradation.

Inhibition of MMP-2 and MMP-9 by Dietary Antioxidants in THP-1 Macrophages and Sera from Patients with Breast Cancer.

Polyphenols, the main antioxidants of diet, have shown anti-inflammatory, antioxidant and anticarcinogenic activities. Here, we compared the effects of four polyphenolic compounds on ROS production and on the levels of matrix metalloproteinase (MMP)-2 and -9, which represent important pathogenetic factors of breast cancer. THP-1 differentiated macrophages were activated by LPS and simultaneously treated with different doses of a green tea extract (GTE), resveratrol (RSV), curcumin (CRC) and an olive fruit extract (oliplus). By using the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, we found that all of the tested compounds showed antioxidant activity in vitro. In addition, GTE, RSV and CRC were able to counteract ROS production induced by H2O2 in THP-1 cells. As assessed by a zymographic analysis of THP-1 supernatants and by an "in-gel zymography" of a pool of sera from patients with breast cancer, the antioxidant compounds used in this study inhibited both the activity and expression of MMP-2 and MMP-9 through different mechanisms related to their structures and to their ability to scavenge ROS. The results of this study suggest that the used antioxidants could be promising agents for the prevention and complementary treatment of breast cancer and other diseases in which MMPs play a pivotal role.

Batimastat Induces Cytotoxic and Cytostatic Effects in In Vitro Models of Hematological Tumors.

The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is well-documented, and these pathologies remain with poor outcomes despite treatment advancements. In this study, we investigated the effects of batimastat (BB-94), an MMP inhibitor (MMPi), in single-administration and daily administration schemes in AML, MDS, and MM cell lines. We used four hematologic neoplasia cell lines: the HL-60 and NB-4 cells as AML models, the F36-P cells as an MDS model, and the H929 cells as a model of MM. We also tested batimastat toxicity in a normal human lymphocyte cell line (IMC cells). BB-94 decreases cell viability and density in a dose-, time-, administration-scheme-, and cell-line-dependent manner, with the AML cells displaying higher responses. The efficacy in inducing apoptosis and cell cycle arrests is dependent on the cell line (higher effects in AML cells), especially with lower daily doses, which may mitigate treatment toxicity. Furthermore, BB-94 activated apoptosis via caspases and ERK1/2 pathways. These findings highlight batimastat's therapeutic potential in hematological malignancies, with daily dosing emerging as a strategy to minimize adverse effects.