Preventive and therapeutic approach for aberrant cell differentiation and isr-associated diseases

A method for the prevention, amelioration and/or treatment of a disease caused by the activation of the integrated stress response (ISR) involving the p-eIF2α pathway in a subject, comprising:

• administering to the subject a modulator of a phosphorylated eukaryotic initiation factor 2α (p-eIF2α), wherein the modulator is represented by Formula I:
• wherein each of R1, R2, R3 and R4 is independently selected from a group consisting of hydrogen, halogen, —OCH3, —OCH2Ph, —C(O)Ph, —CH3, —CF3, —CCl3, —CN, —S(O)CH3, —OH, —NH2, —COOH, —CONH2, —NO2, —C(O)CH3, —CH(CH3)2, —CCSi(CH3)3, —CCH, —CH2CCH, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O) NHNH2, —NHC═(O)NH2, —NHSO2H, —NHC═(O) H, —NHOH, —OCF3, —OCHF2, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
• or Formula II:
• wherein R1 is pyrrolopyrimidine, which may be unsubstituted or substituted with amino or alkyl;
• R2 is pyridyl, pyrrolyl or pyrazolyl, which may be unsubstituted or substituted with halogen, alkyl or trihaloalkyl;
• and R3 is hydrogen or halogen;
• wherein the disease is selected from the group consisting of cancers, inflammatory diseases, diabetes, fibrosis, obesity, neurodegeneration and skeletal disorders.

A method of preventing and/or ameliorating aberrant cell differentiation in a population of cells, the method comprising a step of contacting the population of cells an effective amount of a molecule that is capable of inhibiting the ectopic expression of Sox9/SOX9 and/or ATF4, wherein the molecule is a small molecule represented by Formula I:

• wherein each of R1, R2, R3 and R4 is independently selected from a group consisting of hydrogen, halogen, —OCH3, —OCH2Ph, —C(O)Ph, —CH3, —CF3, —CCl3, —CN, —S(O)CH3, —OH, —NH2, —COOH, —CONH2, —NO2, —C(O)CH3, —CH(CH3)2, —CCSi(CH3)3, —CCH, —CH2CCH, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O) NHNH2, —NHC═(O)NH2, —NHSO2H, —NHC═(O) H, —NHOH, —OCF3, —OCHF2, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
• or Formula II:
• wherein R1 is pyrrolopyrimidine, which may be unsubstituted or substituted with amino or alkyl;
• R2 is pyridyl, pyrrolyl or pyrazolyl, which may be unsubstituted or substituted with halogen, alkyl or trihaloalkyl;
• and R3 is hydrogen or halogen.