ALK2 Inhibitors Display Beneficial Effects in Preclinical Models of ACVR1 mutant Diffuse Intrinsic Pontine Glioma

This paper identifies the two physicochemically attractive LDN compounds, the most potent LDN193189 and selective LDN214117, as promising lead compounds with efficient inhibition of proliferation and induction of apoptosis in vitro. Additionally, enhanced survival of mice bearing orthotopic ACVR1-mutant patient-derived DIPG xenografts in vivo along with good pharmacokinetics and CNS penetration raises the prospect of ALK2 inhibitors potentially entering clinical trials in the future.

In order to determine the sensitivity of DIPG cells to ALK2 inhibitors, panel of pharmacological inhibitors of ALK2 was observed on ACVR1 mutant and WT cells. 11 compounds in total were included in the panel, which consisted of the compounds based on the pyrazolo[1,5-a]pyrimidine scaffold (dorsomorphin, DMH1, LDN-193189, LDN-212854), a series of pyridine compounds (K02288, LDN-214117, LDN-213844, LDN-213819), as well as clinically ‘approved’ or ‘investigated’ drugs with reported ALK2 inhibitory activity (saracatinib, momelotinib, and perhexiline maleate).

The most potent compound (LDN193189) had GI50 values in the range of 0.70 – 3.16 uM but little selectivity was observed between ACVR1 mutant and WT cells.

The most selective compound (LDN214117) had GI50 value of 1.57 uM for cells with ACVR1-/- R206H whilst 5.83 – 6.23 uM for cells with ACVR1-/- G328V and AVCR1 WT with high pSMAD1/5/8 expression.

The left survival curve shows that the in vivo efficacy of both early ALK2 inhibitors LDN193189 and LDN214117
in 7-10 orthotopic DIPG patient-derived xenograft models. Compared against the vehicle-treated controls, both compounds increased % survival in the tested models, highlighting ALK2 as a potential therapeutic target.
(Carvalho et al., 2019, Communications Biology)

Most recently , an open-source pharmaceutical company called Medicine 4 Kids or M4K Pharma have been developing their compounds derived from LDN214117, hoping to bring them into clinical trials. Therefore, in collaboration with M4K Pharma, I have been performing pre-clinical studies to discover which drug candidates are the most potent against ACVR1 mutant patient-derived cells. This will be elaborated further in my FUTURE POST!

For anyone interested in my NOTES of this journal, please refer to the PDF below.