Targeted protein degradation (TPD) is an alternative to conventional protein inhibition that is gaining attention due to advantages such as ensuring complete elimination of the target protein, reduced off-target effects or the potential to target previously inaccessible or “undruggable” proteins. Proteolysis targeting chimeras (PROTACs) are agents used for TPD that have proven effective for degradation of histone deacetylase (HDAC), among other different proteins.
Right open reading frame kinase 2 (RIOK2) plays an essential role in ribosome assembly and cell growth, survival and stress responses. Research has linked RIOK2 to tumor progression and poor prognosis in several types of cancer such as breast, lung, prostate or hematological tumors.
The absent, small or homeotic-like 1 (ASH1L) protein regulates the expression of HOXA genes, which are critical for the development of MLL1 translocations frequently found in leukemia patients. Knockdown of ASH1L leads to growth arrest and apoptosis of leukemia cells, thereby inhibiting leukemia progression suggesting that ASH1L can be considered as a therapeutic target in this setting.
Hypoxia-inducible factors (HIFs) are crucial to maintain oxygen homeostasis by regulating cellular metabolic adaptation under hypoxia conditions. Depletion of factor inhibiting HIF (FIH), an enzyme that negatively regulates the activity of the HIF-1α isoform, has been associated with reductions in hepatic steatosis and body mass in mice.
Tyrosine-protein phosphatase non-receptor type 1 (PTP1B) acts as a negative regulator of the insulin signaling pathway by dephosphorylating both the insulin receptor (IR) and the insulin receptor substrate, leading to insulin resistance, the most significant characteristic of type 2 diabetes.
Researchers from Beijing Institute of Technology (BIT) and affiliated organizations presented the discovery and preclinical characterization of novel soluble epoxide hydrolase 2 (sEH) inhibitors as candidates for the treatment of inflammatory disorders.
The activation of the adenosine A2A receptor, which is mediated by the inhibition of adenosine A1 receptor, has been associated with depression-like behavior and anhedonia. High levels of cortisol, increased oxidative stress and antioxidant enzyme reduction are also contributors to the pathophysiology of depression.
Parkinson’s disease, characterized by progressive dopamine neuron loss, leads to motor deficits such as bradykinesia and rigidity, as well as nonmotor symptoms like cognitive decline and depression. While L-DOPA alleviates motor symptoms, long-term use often results in side effects, including motor fluctuations and dyskinesias, as well as nonmotor (psychotic-like) side effects.
Son of sevenless homolog 1 (SOS1) is an essential guanine nucleotide exchange factor (GEF) in KRAS-driven tumors, and it also functions as a downstream node protein of BCR-ABL, suggesting its critical role in the pathogenesis of chronic myeloid leukemia (CML). Investigators at Shanghaitech University have reported the discovery and preclinical characterization of a novel potent SOS1 proteolysis targeting chimera (PROTAC) – SIAIS-562055 – being developed as an anticancer agent.
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