The overall structure of CH-4051 is similar to that of methotrexate
(MTX), except CH-4051 has a quinazoline ring and lacks the nitrogens
of the pteridine ring of MTX (in blue below), the tertiary nitrogen
in MTX is replaced with a methylene bridge in CH-4051 and CH-4051 has
an additional methylene group (highlighted in green) on the glutamic
acid side chain.
Because CH-4051 has a quinazoline ring, it does not hydroxylate as
seen below for MTX (in pink), producing 7-hydroxy-methotrexate (7-OH-MTX),
the most common metabolite of MTX and the molecule thought to be responsible
for MTX liver and kidney toxicity.
Because MTX does not have the 4-methylene glutamic acid side chain,
folylpolyglutamate synthetase (FPGS) adds glutamate residues to the
MTX side chain (red).
Up to 7 glutamate moieties can be added to this side chain in a process
called polyglutamylation. The additional size and charge of the
polyglutamylated molecule causes it to be retained in the cell, which
is thought to potentiate the side effects of MTX.