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Halogenation is another class of electrophilic addition reactions where a halogen molecule gets added across a π bond. In alkynes, the presence of two π bonds allows for the addition of two equivalents of halogens (bromine or chlorine). The addition of the first halogen molecule forms a trans-dihaloalkene as the major product and the cis isomer as the minor product. Subsequent addition of the second equivalent yields the tetrahalide.
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Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
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Adolf von Baeyer attempted to explain the instabilities of small and large cycloalkane rings using the concept of angle strain — the strain caused by the deviation of bond angles from the ideal 109.5° tetrahedral value for sp3  hybridized carbons. However, while cyclopropane and cyclobutane are strained, as expected from their highly compressed bond angles, cyclopentane is more strained than predicted, and cyclohexane is virtually strain-free. Hence, Baeyer’s theory that...
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Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
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Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
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Discovery of Conformationally Constrained ALK2 Inhibitors.

Héctor González-Álvarez1,2, Deeba Ensan1,2, Tao Xin1

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Researchers developed novel ALK2 inhibitors with improved potency and selectivity for treating diffuse intrinsic pontine glioma (DIPG). These compounds show promise for future therapeutic development in DIPG.

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Area of Science:

  • Medicinal Chemistry
  • Drug Discovery
  • Oncology

Background:

  • Diffuse intrinsic pontine glioma (DIPG) remains a devastating pediatric brain tumor with limited treatment options.
  • Decades of research have yielded minimal improvement in patient outcomes for DIPG.
  • Targeting aberrant signaling pathways, such as those involving ALK2, is a key strategy in developing new cancer therapies.

Purpose of the Study:

  • To design, synthesize, and evaluate novel ALK2 inhibitors based on scaffold modifications of M4K2009.
  • To explore the impact of rigidification strategies on inhibitor potency and selectivity.
  • To identify potential drug candidates for the treatment of DIPG.

Main Methods:

  • Synthesis of novel ether-linked and amine-linked constrained ALK2 inhibitors.
  • In vitro evaluation of inhibitor potency against ALK2.
  • Assessment of selectivity against related kinases, such as ALK5.
  • Preliminary in vivo pharmacokinetic studies, including blood-brain barrier penetration.

Main Results:

  • Discovery of potent ether-linked inhibitors (M4K2308, M4K2281) and amine-linked inhibitors (M4K2304, M4K2306) of ALK2.
  • Demonstration of superior potency against ALK2 compared to the reference compound.
  • M4K2304 and M4K2306 exhibited exceptional selectivity for ALK2 over ALK5.
  • Favorable in vivo pharmacokinetic profiles, including blood-brain barrier penetration, were observed for the constrained scaffolds.

Conclusions:

  • Novel constrained ALK2 inhibitors with enhanced potency and selectivity have been developed.
  • These compounds represent a promising new chemical space for DIPG therapeutic development.
  • Further optimization and evaluation in orthotopic DIPG models are warranted.