Traditional therapies for relapsed/refractory T-cell malignancies, such as T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphomas, have limited efficacy. Chimeric antigen receptor T-cell (CAR-T) therapy has shown potential in treating hematologic malignancies, but challenges such as tumor immune evasion, CAR-T resistance, and cytokine release syndrome (CRS) hinder its clinical application. In this study, we generated CD7CAR-T^CD7- cells by modifying naturally occurring CD7 negative T cells from human peripheral blood with a novel CD7 targeted CAR construct. The cytotoxic efficacy of CD7CAR-T^CD7- cells against CD7 positive T cell malignancies was assessed through in vitro experiments and xenograft mouse models. To address CAR-T therapy limitations, we identified BAM15, a mitochondrial uncoupling agent, from a small molecule library. BAM15 enhanced the cytotoxic function of CD7CAR-T^CD7- cells in a concentration-dependent manner while reducing cytokine release profile in both cellular assays and xenograft models. Notably, at low concentrations (2.5μM, 1 μM and 0.5 μM), BAM15 improved antitumor efficacy at suboptimal effector-to-target ratios (E:T = 1:1 and 1:2), reduced inflammatory cytokines like IL-6 and TNFα, and alleviated inflammatory cell infiltration in lung and liver. This study confirms the feasibility of constructing CD7CAR-T^CD7- cells from CD7^- T cells and first reveals the synergistic effects of BAM15 on CD7CAR-T^CD7- cells, for overcoming dose limitations and CRS of CAR-T therapy, and providing a novel strategy for T-cell malignancies.

01 Feb 2025·Bioorganic & Medicinal Chemistry

Unsymmetric hydroxylamine and hydrazine BAM15 derivatives as potent mitochondrial uncouplers

Article

Author: Li, Catherine ; Salamoun, Joseph M ; Shrestha, Riya ; Hargett, Stefan ; Beretta, Martina ; Quinlan, Joseph E ; Garcia, Christopher J ; Hoehn, Kyle L ; Santos, Webster L

Chemical mitochondrial uncouplers are protonophoric, lipophilic small molecules that transport protons from the mitochondrial intermembrane space into the matrix independent of ATP synthase, thus uncoupling nutrient oxidation from ATP production. Our previous work identified BAM15 (IC₅₀ 0.27 μM) as a potent and efficacious mitochondrial uncoupler with potential for obesity treatment. In this paper, we investigate in vitro and in vivo properties of hydroxylamine and hydrazine BAM15 derivatives and reveal the high uncoupling nature of these compounds. Our structure-activity relationship studies revealed that the hydroxylamine BAM15 analogs are more potent than hydrazine ones. For example, the most potent of the hydrazine series was 5a with an EC₅₀ value of 4.6 μM and 103 % activity of BAM15 while compound 4e was the best among the hydroxylamine series with EC₅₀ value of 340 nM and 118 % BAM15 mitochondrial uncoupling activity in rat L6 myoblasts. Pharmacokinetic profiling of 5a and 4e revealed low exposure (2-220 nM) and short half-life (15-27 min) in mice.

01 Feb 2025·Neurochemical Research

ATP Restoration by ATP-Deprived Cultured Primary Astrocytes

Article

Author: Dringen, Ralf ; Willker, Johanna Elisabeth ; Watermann, Patrick ; Harders, Antonia Regina ; Karger, Gabriele

AbstractA high cellular concentration of adenosine triphosphate (ATP) is essential to fuel many important functions of brain astrocytes. Although cellular ATP depletion has frequently been reported for astrocytes, little is known on the metabolic pathways that contribute to ATP restoration by ATP-depleted astrocytes. Incubation of cultured primary rat astrocytes in glucose-free buffer for 60 min with the mitochondrial uncoupler BAM15 lowered the cellular ATP content by around 70%, the total amount of adenosine phosphates by around 50% and the adenylate energy charge (AEC) from 0.9 to 0.6. Testing for ATP restoration after removal of the uncoupler revealed that the presence of glucose as exclusive substrate allowed the cells to restore within 6 h around 80% of the initial ATP content, while coapplication of adenosine plus glucose enabled the cells to fully restore their initial ATP content within 60 min. A rapid but incomplete and transient ATP restoration was found for astrocytes that had been exposed to adenosine alone. This restoration was completely prevented by application of the pyruvate uptake inhibitor UK5099, the respiratory chain inhibitor antimycin A or by the continuous presence of BAM15. However, the presence of these compounds strongly accelerated the release of lactate from the cells, suggesting that the ribose moiety of adenosine can serve as substrate to fuel some ATP restoration via mitochondrial metabolism. Finally, the adenosine-accelerated ATP restoration in glucose-fed astrocytes was inhibited by the presence of the adenosine kinase inhibitor ABT-702. These data demonstrate that astrocytes require for a rapid and complete ATP restoration the presence of both glucose as substrate and adenosine as AMP precursor.

News (Medical) associated with BAM-15

05 Jun 2024

·www.echemi.com

"BAM-15 Dosage" Use with Caution

In today's society, "BAM-15 dosage" is becoming a focus for many people. This supplement claims to bring various benefits, but its "BAM-15 dosage" usage method is highly controversial. As a new supplement, "BAM-15 dosage" is popular among consumers. It claims to enhance body functions and improve various health indicators. However, excessive use of "BAM-15 dosage" may have adverse effects on one's health. Therefore, when using "BAM-15 dosage," we must pay special attention to the correct "BAM-15 dosage." Many people using "BAM-15 dosage" often ignore the dosage recommendations on the instructions and blindly increase their intake of "BAM-15 dosage." This not only may cause discomfort but also may trigger some serious side effects. Therefore, we must follow the advice of professionals and take "BAM-15 dosage" at the right time and in the right amount to ensure our health. Moreover, long-term use of "BAM-15 dosage" also needs to be taken seriously. Overreliance on "BAM-15 dosage" may damage the body's regulation mechanism. Therefore, when using "BAM-15 dosage," we must maintain moderation and stop taking it at appropriate times to maintain the body's health balance. In summary, the use of "BAM-15 dosage" requires extra caution. We must follow professional advice, take it at the right time and in the right amount, and stop taking it at appropriate times to ensure our health. Only in this way can we fully enjoy the benefits of "BAM-15 dosage".

100 Deals associated with BAM-15

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United States	Stanford University School of Medicine	04 Apr 2023
Acute kidney injury due to sepsis	Preclinical	United States	National Institute of Diabetes & Digestive & Kidney Diseases	05 Nov 2019
Reperfusion Injury	Preclinical	United States	Seahorse Bioscience, Inc.	01 Apr 2014
Reperfusion Injury	Preclinical	United States	University of Virginia	01 Apr 2014
Insulin Resistance	Preclinical	Australia	The Garvan Institute of Medical Research	-
Obesity	Preclinical	Australia	The Garvan Institute of Medical Research	-
Sarcopenia	Discovery	Australia	The Garvan Institute of Medical Research	-

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