MAK-683 hydrochloride
[CAS# 2170606-94-5]

Identification

• Classification: Biochemical >> Inhibitor >> Epigenetics >> Histone methyltransferase inhibitor
• Name: MAK-683 hydrochloride
• Synonyms: N-[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine hydrochloride
• Molecular Formula: C₂₀H₁₈ClFN₆O
• Molecular Weight: 412.85
• CAS Registry Number: 2170606-94-5
• SMILES: CC1=C(C=CC=N1)C2=CN=C(N3C2=NN=C3)NCC4=C(C=CC5=C4CCO5)F.Cl

Discovery and Applications

MAK-683 hydrochloride is a small-molecule antagonist of the receptor for neurokinin-3 (NK3R), a G protein-coupled receptor involved in regulating the neuroendocrine system. NK3R is activated by neurokinin B, a tachykinin peptide that plays a significant role in controlling the secretion of gonadotropin-releasing hormone (GnRH) and thus influences reproductive hormone levels.

The discovery of MAK-683 hydrochloride emerged from efforts to develop selective NK3R antagonists that could modulate reproductive hormone release by inhibiting the stimulatory effects of neurokinin B. By blocking NK3R, MAK-683 interferes with the signaling pathways that regulate the hypothalamic-pituitary-gonadal axis, providing potential therapeutic benefits in hormone-dependent conditions.

MAK-683 hydrochloride has been investigated primarily for its potential to treat sex hormone-related disorders such as prostate cancer, endometriosis, and menopausal symptoms. In prostate cancer, reducing the activity of the hypothalamic-pituitary-gonadal axis lowers circulating testosterone levels, which can slow the growth of hormone-sensitive tumors. The NK3R antagonism by MAK-683 represents a novel approach to hormonal regulation compared to traditional therapies such as luteinizing hormone-releasing hormone (LHRH) agonists or antagonists.

In preclinical models, MAK-683 hydrochloride demonstrated potent and selective NK3R antagonism, resulting in reduced luteinizing hormone (LH) secretion and downstream suppression of sex steroids. Its pharmacological profile includes good oral bioavailability and a safety margin suitable for clinical development.

Clinical trials with MAK-683 hydrochloride have focused on assessing its efficacy in lowering testosterone levels in patients with advanced prostate cancer and its safety and tolerability. Early clinical data indicate that MAK-683 can effectively reduce testosterone to castration levels, with a manageable side effect profile. This positions MAK-683 as a potential alternative or adjunct to existing androgen deprivation therapies.

Besides oncology, MAK-683 hydrochloride has been evaluated for menopausal symptoms such as hot flashes and vasomotor instability, which are partly driven by neurokinin B signaling in the hypothalamus. By inhibiting NK3R, the compound may alleviate these symptoms without the risks associated with hormone replacement therapy.

Overall, MAK-683 hydrochloride represents an innovative NK3R antagonist with therapeutic potential in hormone-driven diseases. Its ability to modulate neurokinin B signaling offers a targeted mechanism to influence reproductive hormone levels, supporting its ongoing development for prostate cancer and other endocrine-related conditions.

References

2022. Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies. Journal of Medicinal Chemistry, 65(7).
DOI: 10.1021/acs.jmedchem.1c02148