Discovery of Conformationally Constrained ALK2 Inhibitors.

Despite decades of research on new diffuse intrinsic pontine glioma (DIPG) treatments, little or no progress has been made on improving patient outcomes. In this work, we explored novel scaffold modifications of , a 3,5-diphenylpyridine ALK2 inhibitor previously reported by our group. Here we disclose the design, synthesis, and evaluation of a first-in-class set of 5- to 7-membered ether-linked and 7-membered amine-linked constrained inhibitors of ALK2.

The Imipridone ONC213 Targets α-Ketoglutarate Dehydrogenase to Induce Mitochondrial Stress and Suppress Oxidative Phosphorylation in Acute Myeloid Leukemia.

Unlabelled: Eradication of acute myeloid leukemia (AML) is therapeutically challenging; many patients succumb to AML despite initially responding to conventional treatments. Here, we showed that the imipridone ONC213 elicits potent antileukemia activity in a subset of AML cell lines and primary patient samples, particularly in leukemia stem cells, while producing negligible toxicity in normal hematopoietic cells. ONC213 suppressed mitochondrial respiration and elevated α-ketoglutarate by suppressing α-ketoglutarate dehydrogenase (αKGDH) activity.

Design, Synthesis, and Characterization of 4-Aminoquinazolines as Potent Inhibitors of the G Protein-Coupled Receptor Kinase 6 (GRK6) for the Treatment of Multiple Myeloma.

Both previous and additional genetic knockdown studies reported herein implicate G protein-coupled receptor kinase 6 (GRK6) as a critical kinase required for the survival of multiple myeloma (MM) cells. Therefore, we sought to develop a small molecule GRK6 inhibitor as an MM therapeutic. From a focused library of known kinase inhibitors, we identified two hits with moderate biochemical potencies against GRK6.

Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of C-Labeled ALK2 Inhibitors.

Mutations in the gene encoding activin receptor-like kinase 2 (ALK2) are implicated in the pathophysiology of a pediatric brainstem cancer, diffuse intrinsic pontine glioma (DIPG). Inhibitors of ALK2 that cross the blood-brain barrier have been proposed as a method of treatment for DIPG. As part of an open science approach to radiopharmaceutical and drug discovery, we developed C-labeled radiotracers from potent and selective lead ALK2 inhibitors to investigate their brain permeability through positron emission tomography (PET) neuroimaging.

Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma.

There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease.

Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma.

Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant.

1-(Bicyclopiperazinyl)ethylindoles and 1-(homopiperazinyl)ethyl-indoles as highly selective and potent 5-HT(7) receptor ligands.

A novel series of 1-(bicyclopiperazinyl)ethylindole and 1-(homopiperazinyl)ethyl-indole derivatives was synthesized and found to be potent and selective 5-HT(7) receptor ligands.

Diastereoselection during 1,2-Addition of the Allylindium Reagent to alpha-Thia and alpha-Amino Aldehydes in Aqueous and Organic Solvents.

The stereochemistry of the indium-promoted reaction of allyl bromide with alpha-thia (PhS and MeS), disubstituted alpha-amino (Bn(2)N, Me(2)N, isoindolyl), and protected alpha-amino aldehydes (Ac and Boc) in water has been evaluated. The reactions involving the sulfur derivatives are minimally diastereoselective, indicating that the allylindium reagent is not thiophilic. Chelation is not observed and pi-facial discrimination is achieved via Felkin-Ahn transition states under the steric control of the substituents.

Factors Influencing 1,4-Asymmetric Induction during Indium-Promoted Coupling of Oxygen-Substituted Allylic Bromides to Aldehydes in Aqueous Solution.

The preparation and indium-promoted aldehyde addition reactions of a series of 3-substituted 3-oxy-1-bromo-2-methylidenepropanes under aqueous conditions are described. The (tert-butyldimethylsilyl)oxy derivatives 4a-d are the most diastereoselective of this group of reagents, giving rise to levels of syn-1,4-asymmetric induction in the range of 87-99%. Interestingly, syn stereoselectivity is eroded and reactions proceed more rapidly when the steric bulk of the oxygen substituent is reduced as in the hydroxy and methoxy derivatives.