M4K2009

M4K2009 refers to a small-molecule inhibitor targeting the ALK2 (ACVR1) kinase, which is implicated in certain cancers and rare diseases like diffuse intrinsic pontine glioma (DIPG). M4K2009 was developed as part of an open science initiative to create selective ALK2 inhibitors. While it demonstrated high selectivity for ALK2 over ALK5, it also showed moderate activity against the hERG potassium channel, raising potential cardiac safety concerns. PMC+1PubMed

To address these off-target effects, researchers modified the compound's structure, leading to the development of analogues like M4K2149, which maintained potency against ALK2 while reducing unwanted interactions. PubMed

Biochemical and Cellular Potency

• Potent inhibition of ALK2: M4K2009 is a strong type I inhibitor of ALK2, showing high potency in biochemical kinase assays and functional cellular assays. It is effective against both wild-type (WT) and disease-related mutant forms of ALK2—such as G328V, R206H, and R258G—in both biochemical and cell-based settings PMC+1.

• Selectivity within TGF-β family: Notably, M4K2009 is highly selective over ALK5 (the TGF-β receptor), indicating a strong preference for ALK2 PubMedRCSB PDB.

Pharmacokinetic and ADME Profile

• M4K2009 was developed through an open-science initiative and optimized for oral bioavailability and brain penetration, enabling activity within the central nervous system—an especially critical feature for targeting conditions like diffuse intrinsic pontine glioma (DIPG) PubMedReaction Biology.

• It demonstrates robust in vivo pharmacokinetics (PK) and good tolerability, marking it as a promising preclinical candidate for further evaluation in orthotopic (brain-based) tumor models Reaction BiologyRCSB PDB.

Off-Target Activity and Safety Considerations

• Moderate activity against the hERG channel: While highly selective for ALK2, M4K2009 also shows moderate inhibition of the hERG potassium channel, which is a known liability related to cardiac safety (risk of arrhythmia) PubMedRCSB PDB.

• To reduce such off-target effects, analogues like M4K2149 were developed: these maintain potent ALK2 inhibition while exhibiting reduced hERG activity PubMed.

Preclinical Application—DIPG Focus

• The compound emerged from a focused open scholar-driven effort to target DIPG, a pediatric brain tumor with few effective treatments. M4K2009’s CNS penetration, potency, and oral drug-like properties make it a suitable candidate for in vivo evaluation in DIPG models Reaction BiologyPubMed.

• Preliminary studies indicate significant efficacy in relevant preclinical models, such as those representing ACVR1-mutant DIPG, suggesting therapeutic promise in this context SynapseReaction Biology.

0C Short Term -20C Long Term

M4K2009; M4K-2009; M4K 2009

1) Ensan D, Smil D, Zepeda-Velázquez CA, Panagopoulos D, Wong JF, Williams EP, Adamson R, Bullock AN, Kiyota T, Aman A, Roberts OG, Edwards AM, O'Meara JA, Isaac MB, Al-Awar R. Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma. J Med Chem. 2020 May 14;63(9):4978-4996. doi: 10.1021/acs.jmedchem.0c00395. Epub 2020 May 5. PMID: 32369358.