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Last update 23 Jan 2025

LDHB

Last update 23 Jan 2025

Basic Info

Synonyms

L-lactate dehydrogenase B chain, lactate dehydrogenase B, LDH heart subunit

+ [4]

Introduction

Interconverts simultaneously and stereospecifically pyruvate and lactate with concomitant interconversion of NADH and NAD(+).

Drugs associated with LDHB

Galloflavin

Target

LDHA x LDHB

Mechanism

LDHA inhibitors [+1]

Active Org.

Alma Mater Studiorum - Università di Bologna

Originator Org.

Alma Mater Studiorum - Università di Bologna

Active Indication

Breast Cancer

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

AXKO-0046

Target

LDHB

Mechanism

LDHB inhibitors

Active Org.

Axcelead Drug Discovery Partners, Inc.Startup

Originator Org.

Axcelead Drug Discovery Partners, Inc.Startup

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

MS-6105

Target

LDHA x LDHB

Mechanism

LDHA inhibitors [+1]

Active Org.

Icahn School of Medicine at Mount Sinai

Originator Org.

Icahn School of Medicine at Mount Sinai

Active Indication

Pancreatic Cancer

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with LDHB

100 Translational Medicine associated with LDHB

0 Patents (Medical) associated with LDHB

973

Literatures (Medical) associated with LDHB

01 Feb 2025·Experimental Neurology

Diminished lactate utilization in LDHB-deficient neurons leads to impaired long-term memory retention

Article

Author: Lee, Jin Soo ; Han, Songmi ; Yoon, Bok Seon ; Kim, Yihyang ; Park, Chan Bae

Neurons' high energy demands for processing, transmitting, and storing information in the brain necessitate efficient energy metabolism to maintain normal neuronal function. The astrocyte-neuron lactate shuttle (ANLS) hypothesis suggests neurons preferentially use lactate from astrocytes over glucose for energy. This study investigated lactate dehydrogenase B (LDHB), which preferentially converts lactate to pyruvate, in neuronal energy metabolism and cognitive function. LDHB-deficient neurons showed reduced lactate-driven energy metabolism in culture, while LDHB-deficient brains accumulated lactate, both indicating decreased lactate utilization. This reduced lactate utilization was correlated with impaired long-term memory in LDHB-deficient mice, while short-term memory remained unaffected and overall neuropathology was only mildly disturbed. Unexpectedly, LDHB-deficient neurons maintain stable energy metabolism under physiological glucose conditions, indicating the presence of lactate dehydrogenase (LDH) activity in LDHB-deficient neurons. The observation of lactate dehydrogenase A (LDHA), which preferentially converts pyruvate to lactate but can also catalyze the reverse reaction less efficiently, in LDHB-deficient neurons may explain their stable energy metabolism and reduced lactate utilization. This study challenges the established concept of strict LDH isoform compartmentalization in brain cells, questioning the exclusive presence of LDHB in neurons and suggesting a more flexible neuronal metabolic profile than previously assumed by the ANSL hypothesis.

01 Feb 2025·European Journal of Medicinal Chemistry

Synthesis of 1-Hydroxy(and 1-Alkoxy, 1-Acyloxy)-1H-indoles and evaluations of their suppressive activities against tumor growth through inhibiting lactate dehydrogenase A

Article

Author: Yang, Eun-Sun ; Kim, Ye Eun ; Kim, Chorong ; Kim, Bo-Sung ; Park, Wonyoung ; Cheon, Se-Yun ; Bae, Chang-Hwan ; Jin, Jung-Sook ; Lim, Yoo Jin ; Cho, Hyunsung ; Kim, Seungtae ; Lee, Sang Hyup ; Ha, Ki-Tae

Inhibition of lactate dehydrogenase (LDH) has emerged as a promising cancer therapy strategy due to its essential role in the metabolic transformation of cancer cells. In this study, 53 derivatives of 1-hydroxy(and 1-alkoxy, 1-acyloxy)indoles were designed, synthesized, and biologically evaluated. Several multi-substituted 1-hydroxy(and 1-alkoxy, 1-acyloxy)indole compounds exhibited inhibitory activity against the LDH-A isoform (LDHA). We confirmed that the C(3)-substituent provided additional significant hydrogen bonding and hydrophobic interactions, which enhanced the LDHA inhibitory activity with high selectivity. Our results revealed that methyl 4-bromo-3-[(n-hexyloxy)methyl]-1-hydroxy-1H-indole-2-carboxylate (1g), selectively inhibited LDHA (IC₅₀ = 25 ± 1.12 nM) without affecting the LDH-B isoform (LDHB). The compound exhibited potent cytotoxic activity in several cancer cell lines, including DLD-1 colorectal cancer cells (GI₅₀ = 27 ± 1.2 μM). Compound 1g significantly inhibited cancer cell growth by activating apoptotic pathways in a xenograft cancer model, without causing weight loss or liver and kidney damage. Therefore, compound 1g may serve as a highly specific and promising candidate for the development of LDHA inhibitors for cancer therapy.

01 Feb 2025·Redox Biology

Hydrogen sulfide attenuates disturbed flow-induced vascular remodeling by inhibiting LDHB-mediated autophagic flux

Article

Author: Zhang, Yongya ; Huang, Xiying ; He, Ben ; Wang, Xia ; Li, Long ; Huo, Huanhuan ; Shen, Linghong ; Zhou, Guo

Disturbed flow (DF) plays a critical role in the development and progression of cardiovascular disease (CVD). Hydrogen sulfide (H₂S) is involved in physiological processes within the cardiovascular system. However, its specific contribution to DF-induced vascular remodeling remains unclear. Here, we showed that the H₂S donor, NaHS suppressed DF-induced vascular remodeling in mice. Further experiments demonstrated that NaHS inhibited the proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor-BB (PDGF), as well as the autophagy triggered by DF and PDGF. Mechanistically, RNA-Seq results revealed that NaHS counteracted the PDGF-induced upregulation of lactate dehydrogenase B (LDHB). Overexpression of LDHB abolished the protective effect of NaHS on DF-induced vascular remodeling. Furthermore, LDHB interacted with vacuolar-type proton ATPase catalytic subunit A (ATP6V1A), leading to lysosomal acidification, a process that was attenuated by NaHS treatment. The residues of leucine (Leu) 57 in ATP6V1A and serine (Ser) 269 in LDHB are critical for their interaction. Notably, the expression of LDHB was found to be elevated in vascular tissues from patients with abdominal aortic aneurysms (AAA) and thoracic aortic aneurysms (TAA). These data identify a molecular mechanism by which H₂S attenuates DF-induced vascular remodeling by inhibiting LDHB and disrupting the interaction between LDHB and ATP6V1A, thereby impeding the autophagy process. Our findings provide insight that H₂S or targeting LDHB has therapeutic potential for preventing and treating vascular remodeling.

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LDHB

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