Inhibitors of phosphoglycerate dehydrogenase (PHGDH) and uses thereof
Inventors
Sabatini, David M. • Pacold, Michael • Boxer, Matthew B. • ROHDE, JASON M. • Brimacombe, Kyle R. • Shen, Min • Bantukallu, Ganesha • Liu, Li
Assignees
Dana Farber Cancer Institute Inc • Howard Hughes Medical Institute • Whitehead Institute for Biomedical Research • US Department of Health and Human Services
Publication Number
US-11225469-B2
Publication Date
2022-01-18
Expiration Date
2036-01-15
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Abstract
The present invention provides compounds of Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, pro-drugs, and compositions thereof. Also provided are methods and kits involving the compounds of Formula (I), (II) or (III) for treating diseases associated with the over-expression of phosphoglycerate dehydrogenase (PHGDH) in a subject, such as proliferative diseases (e.g., cancers (e.g., breast cancer, ER negative breast cancer, melanoma, cervical cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases). Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the activity of PHGDH or inhibit the serine biosynthetic pathway, or both.
Core Innovation
The invention provides novel compounds of Formulas (I), (II), and (III), including pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and pro-drugs thereof, which act as inhibitors of phosphoglycerate dehydrogenase (PHGDH). These compounds are useful in the treatment and prevention of diseases associated with over-expression or aberrant activity of PHGDH, such as proliferative diseases including various cancers (breast cancer, ER negative breast cancer, melanoma, cervical cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, autoimmune diseases, and fibrotic diseases (idiopathic pulmonary fibrosis, nephrogenic systemic fibrosis, scleroderma). The inhibitors function by inhibiting PHGDH activity, inhibiting the serine biosynthetic pathway, or both, thereby potentially reducing cell growth or inducing cell death.
The problem addressed by the invention arises from the critical role of PHGDH in the serine biosynthetic pathway, particularly in cancers where PHGDH is over-expressed, such as approximately 70% of ER negative breast cancers and about 5% of melanomas. PHGDH catalyzes the first and rate-limiting step in serine biosynthesis from glucose, essential for nucleotide synthesis and cell proliferation. Existing therapeutic strategies targeting enzymes involved in one-carbon metabolism, such as antifolates, demonstrate efficacy but lack selective inhibitors of PHGDH. The invention solves the need for chemotherapeutics and methods specifically targeting PHGDH to treat cancers and associated diseases characterized by PHGDH over-expression or dependency.
The invention also includes pharmaceutical compositions, kits, and methods of synthesizing these compounds. Methods of use encompass administration of these compounds to subjects or contacting biological samples to inhibit PHGDH activity, serine production, cell growth, or induce cell death selectively in PHGDH-dependent cells. Furthermore, the compounds serve as research tools to study biological pathways related to PHGDH and the serine biosynthetic pathway, enabling diagnostic tests to determine PHGDH over-expression or gene copy number amplification in cancers, guiding patient treatment.
Claims Coverage
The claims include independent claims directed to compounds of Formula (II), pharmaceutical compositions comprising such compounds, methods of treating diseases by administering these compounds, and methods of inhibiting PHGDH activity or inducing cell death in PHGDH-dependent cells using these compounds. Multiple specific compound structures and their uses are claimed.
Compounds of Formula (II) with defined chemical moieties
Claim covers compounds having the chemical structure represented by Formula (II) with specified groups W2, L2, L4, A2, R1-R6, Ra-Rf, and constraints on substituents, excluding certain compounds explicitly listed.
Pharmaceutical compositions comprising compounds of Formula (II)
Compositions containing a compound of Formula (II) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient for therapeutic use.
Methods of treating diseases using compounds of Formula (II)
Methods of treating diseases in subjects by administering therapeutically effective amounts of compounds of Formula (II), including specific diseases such as pulmonary fibrosis, renal cell carcinoma, and breast cancer.
Methods of inhibiting PHGDH activity with Formula (II) compounds
Methods for inhibiting PHGDH activity in subjects or biological samples by administering or contacting with effective amounts of compounds of Formula (II).
Methods of inducing cell death in PHGDH-dependent cells using Formula (II) compounds
Methods for inducing cell death selectively in PHGDH-dependent cells in subjects or biological samples by administering or contacting with compounds of Formula (II).
Methods of treating diseases using selected compounds
Methods of treating diseases using specific compounds as listed in the claims, including similar diseases as above.
Methods of inhibiting PHGDH and inducing cell death using selected compounds
Methods for inhibiting PHGDH activity or inducing cell death using specific selected compounds listed in the claims.
The independent claims primarily focus on compounds of Formula (II) with defined chemical groups, their pharmaceutical compositions, and their use in treating diseases by inhibiting PHGDH activity or inducing cell death in PHGDH-dependent cells. The claims also enumerate specific exemplary compounds and their applications.
Stated Advantages
Selective toxicity of the compounds towards PHGDH-overexpressing, PHGDH-dependent cancer cell lines, with substantially less toxicity towards non-overexpressing cells.
Effective inhibition of PHGDH activity leading to reduction of serine synthesis and cell proliferation in vitro and in vivo.
Favorable ADME properties and solubility demonstrated for compounds such as NCT-502 and NCT-503.
Capability to inhibit serine biosynthesis pathway flux and induce necrosis in PHGDH-dependent tumors without affecting weight or health of treated animals.
Use in the diagnosis and selection of patients with PHGDH-overexpressing cancers for targeted therapy.
Documented Applications
Treatment and prevention of proliferative diseases including breast cancer, ER negative breast cancer, melanoma, and cervical cancer.
Treatment and prevention of fibrotic diseases such as idiopathic pulmonary fibrosis, nephrogenic systemic fibrosis, and scleroderma.
Selective inhibition of PHGDH activity and the serine biosynthetic pathway in subjects or biological samples.
Induction of cell death selectively in PHGDH-dependent cells in subjects or biological samples.
Use as research tools to study PHGDH expression, serine biosynthesis, and related metabolic pathways in diseases.
Diagnostic methods to determine if cancer over-expresses PHGDH or has gene amplification for selecting treatment strategies.
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