The present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods of use thereof for treating cellular proliferative disorders (e.g., cancer).

Disclosed are crystalline forms of sepiapterin free base selected from polymorphs A, B, C, D, E, F, and G, and combinations thereof, as well as crystalline polymorphs of salts of sepiapterin. Also disclosed are pharmaceutical compositions containing one or more such polymorphs and methods for preparing such polymorphs. Sepiapterin is useful in the treatment of a number diseases associated with low cellular levels of BH4, for example, phenylketonuria.

Disclosed are crystalline forms of sepiapterin free base selected from polymorphs A, B, C, D, E, F, and G, and combinations thereof, as well as crystalline polymorphs of salts of sepiapterin. Also disclosed are pharmaceutical compositions containing one or more such polymorphs and methods for preparing such polymorphs. Sepiapterin is useful in the treatment of a number diseases associated with low cellular levels of BH4, for example, phenylketonuria.

The disclosure relates generally to gamma polyglutamated lometrexol compositions, including delivery vehicles such as liposomes containing the gamma polyglutamated lometrexol, and methods of making and using the gamma polyglutamated lometrexol compositions to treat hyperproliferative disorders (e.g., cancer) and disorders of the immune system (e.g., inflammation and autoimmune diseases such as rheumatoid arthritis).

The invention relates to amorphous folate salt. The salt consists of a folate anion and an organic cation. The folate anion is selected from the group consisting of 5-formyl-(6S)-tetrahydrofolic acid, 10-formyl-(6R)-tetrahydrofolic acid, 5-methyl-(6S)-tetrahydrofolic acid, (6S)-tetrahydrofolic acid, 5,10-Methylene-(6R)-tetrahydrofolic acid, and its oxidized derivatives JK12A and Mefox, and the cation is an organic compound selected from the group arginine, choline, acetylcholine, 1,1-dimethyl-biguanidin phenylethylbiguanidin, betaine-methylester and dimethylaminoethanol. The cation is an organic compound with a complementary pharmacological activity.

PROTACs (PROteolysis TArgeting Chimeras) are an emerging class of promising therapeutic modalities that degrade intracellular protein targets by hijacking the cellular ubiquitin-proteasome system. However, potential toxicity of PROTACs in normal cells due to off-tissue on-target degradation effect limits their clinical applications. Precise control of PROTAC's on-target degradation activity in a tissue selective manner could minimize potential toxicity/side-effects. To this end, we developed a cancer cell selective delivery strategy for PROTACs by conjugating a folate group to ubqiquitin recruitment moiety to achieve targeted degradation of proteins of interest (POIs) in cancer cells versus normal cells. We show that our folate-PROTACs, including BRD PROTAC (Folate-ARV-771), MEK PROTAC (Folate-MS432) and ALK PROTAC (Folate-MS99, Folate-S2-MS4048) are capable of degrading BRDs, MEKs and ALK, respectively, in a folate receptor-dependent manner. This design provides a generalizable platform for PROTACs to achieve selective degradation of proteins of interest (POIs) in cancer cells.

PROTACs (PROteolysis TArgeting Chimeras) are an emerging class of promising therapeutic modalities that degrade intracellular protein targets by hijacking the cellular ubiquitin-proteasome system. However, potential toxicity of PROTACs in normal cells due to off-tissue on-target degradation effect limits their clinical applications. Precise control of PROTAC's on-target degradation activity in a tissue selective manner could minimize potential toxicity/side-effects. To this end, we developed a cancer cell selective delivery strategy for PROTACs by conjugating a folate group to ubqiquitin recruitment moiety to achieve targeted degradation of proteins of interest (POIs) in cancer cells versus normal cells. We show that our folate-PROTACs, including BRD PROTAC (Folate-ARV-771), MEK PROTAC (Folate-MS432) and ALK PROTAC (Folate-MS99, Folate-S2-MS4048) are capable of degrading BRDs, MEKs and ALK, respectively, in a folate receptor-dependent manner. This design provides a generalizable platform for PROTACs to achieve selective degradation of proteins of interest (POIs) in cancer cells.

A method for preparing an L-erythrobiopterin compound is provided. The L-erythrobiopterin compound has a structure represented by formula (I), and is mainly prepared from a compound having a structure represented by formula (II) or (III) through dihydroxylation. The preparation method of the L-erythrobiopterin compound is high in production efficiency, low in cost, environmentally friendly, and suitable for industrial production.

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The present invention is directed to a crystalline sodium salt of 5-methyl-(6S)-tetrahydrofolic acid wherein the molar ratio of 5-methyl-(6S)-tetrahydrofolic acid to sodium is from 1:1.51 to 1:2.5 and/or hydrates and/or solvates thereof, as well as, a process of obtaining the same.

The present invention is directed to a crystalline sodium salt of 5-methyl-(6S)-tetrahydrofolic acid wherein the molar ratio of 5-methyl-(6S)-tetrahydrofolic acid to sodium is from 1:1.51 to 1:2.5 and/or hydrates and/or solvates thereof, as well as, a process of obtaining the same.