Allosteric TS Inhibitors Overstabilize Dimer Interface
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Solution Overview
Problem
Current chemotherapy agents targeting thymidylate synthase (TS) often induce resistance and protein overexpression, limiting their effectiveness in treating cancers with aberrant TS overexpression, such as colon, lung, and pancreatic cancers.
Innovation Solution
Development of small molecule allosteric inhibitors that disrupt TS cooperativity by overstabilizing the dimer structure, preventing catalysis without interfering with TS-mRNA binding, thereby avoiding resistance induction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If fluoropyrimidine TS inhibitors are used to target thymidylate synthase, then TS inhibition is achieved and patient survival is prolonged, but TS overexpression is induced and resistance develops
Solution Approach 1:
The patent inverts the conventional approach by using allosteric inhibitors that bind to a different site on TS (the dimer interface) rather than the active site. This alternative binding mode stabilizes the inactive dimer conformation, preventing catalysis without triggering the resistance mechanism associated with active site inhibition.
Solution Approach 2:
The allosteric inhibitors act as intermediaries that indirectly prevent catalysis by stabilizing the dimer interface, rather than directly blocking the active site. This indirect mechanism avoids the induction of TS overexpression that occurs with direct active site inhibitors.
2Reliability
If conventional TS inhibitors are used, then catalytic activity is blocked, but TS-mRNA binding is interfered with leading to resistance
Solution Approach 1:
The patent applies local quality by targeting a specific local region (the dimer interface) rather than the global active site. The allosteric inhibitors bind locally at the dimer interface to stabilize the inactive conformation, achieving enzyme inhibition without interfering with TS-mRNA binding at other locations.
Solution Approach 2:
The patent segments the TS enzyme into functionally distinct regions: the dimer interface (targeted by allosteric inhibitors) and the active site (involved in catalysis and mRNA binding). By targeting only the dimer interface, the inhibitors achieve catalysis blockade without affecting mRNA binding.
3Reliability
If TS is inhibited through active site binding, then catalysis is prevented, but protein overexpression is induced
Solution Approach 1:
The patent inverts the conventional inhibition strategy by stabilizing the inactive dimer conformation through allosteric binding at the interface, rather than blocking the active site. This inverted approach prevents catalysis without triggering the cellular response that leads to TS protein overexpression.
Solution Approach 2:
The patent replaces the mechanical blocking of the active site with a conformational stabilization mechanism. Instead of physically obstructing substrate access, the allosteric inhibitors induce and stabilize the inactive dimer conformation, achieving catalytic inhibition through conformational control rather than steric blocking.
Data Source
AI summary
The current invention is directed to a class of compounds that inhibit the function of Thymidylate synthase. Thymidylate synthase inhibition was noted to result in inhibition of tumor cell grow and killing of tumor cells. Thymidylate synthase inhibition is, thus, useful for treatment of various types of cancers, including but not limited to, acute lymphoblatic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia, large cell immunoblastic lymphoma, plasmacytoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, brain cancer, lung cancer, central nervous system (CNS) cancer, melanoma, renal cancer, prostate cancer, colon cancer, ovarian cancer and breast cancer. The compounds disclosed herein can be used alone or in combination with other cancer treatment regimens (e.g., radiation therapy and/or other chemotherapeutic agents that are administered to a subject having a tumor, cancer or neoplasia).