INCB59872

The advent of LSD1 inhibitor-based clinical utility began with tranylcypromine, and it is now considered an inevitable scaffold in the search for other irreversible novel LSD1 inhibitors (IMG-7289 or bomedemstat, ORY1001 or iadademstat, ORY-2001 or vafidemstat, GSK2879552, and INCB059872). Moreover, numerous reversible inhibitors for LSD1 have been reported in the literature, including clinical candidates CC-90011 (pulrodemstat) and SP-2577 (seclidemstat)...For the first time, we comprehensively organized the peptide-based LSD1 inhibitors from the design strategy. Peptide inhibitors of LSD1 are classified as H3 peptide and SNAIL1 peptide derivatives, along with miscellaneous peptides that include naturally occurring LSD1 inhibitors.

P1/2, N=70, Terminated, Incyte Corporation | Completed --> Terminated; Study terminated by Sponsor

The high response rate of AML patients receiving venetoclax in combination with azacitidine as first line AML therapy means differentiation therapy with LSD1 inhibitors would be more acceptable either in combination with venetoclax, or post-venetoclax treatment. Venetoclax resistant MLL-AF9 driven AML was also resistant to INCB059872, but the combination of venetoclax and INCB059872 was able to slow the onset of venetoclax resistant MLL-AF9 driven AML significantly. The data presented here suggest that inhibition of LSD1 with INCB059872 may alter the expression of apoptotic machinery of AML cells leading to combinatorial therapeutic benefit when co-administered with venetoclax, and that INCB059872 combined with venetoclax may overcome acquired venetoclax resistance in AML.

Carefully designed preclinical studies selected several epigenetic drugs, including inhibitors of DNA methyltransferase (DNMTIs), such as Decitabine, histone deacetylase classes I-II (HDACIs), as Entinostat, Belinostat, lysine-specific histone demethylase (LSD1), as INCB059872 or FT-2102, inhibitors of isocitrate dehydrogenases, and enhancer of zeste homolog 2 (EZH2), such as EPZ6438 and Tamezostat. To enhance the therapeutic effect, the prevalent approach in phase II trial is the association of these epigenetic drug inhibitors, with targeted therapy or immune checkpoint blockade. Optimization of drug dosing and regimens of phase II trials may improve the clinical efficiency of such novel therapeutic approaches against these devastating cancers.