Crystalline CD73 Inhibitor Polymorphs for Cancer Therapy
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Solution Overview
Problem
Current treatments for cancer, particularly those targeting CD73, face challenges in effectively inhibiting the immune-suppressive CD73 pathway, which promotes tumor growth and immune evasion, leading to limited therapeutic efficacy.
Innovation Solution
Development of crystalline forms of 5-[5-[2-isopropylcyclopropyl]-6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione, which inhibit CD73 activity, are used in pharmaceutical compositions to treat cancer, including combinations with other anti-tumor agents and immuno-oncology agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD73 inhibitors are used to block the immune-suppressive pathway, then antitumor immunity is enhanced, but therapeutic efficacy is limited due to the complexity of the CD73 pathway and tumor microenvironment
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline forms (polymorphs) of the CD73 inhibitor compound. Different crystal forms exhibit varying properties such as solubility, stability, and bioavailability, allowing optimization of therapeutic efficacy while maintaining the same chemical structure. This enables tailored selection of crystal forms based on specific treatment requirements and delivery routes.
Solution Approach 2:
The patent employs composite material strategies by formulating the crystalline CD73 inhibitor with various excipients, carriers, and adjuvants to create pharmaceutical compositions. These composite formulations enhance the overall therapeutic effect by improving drug stability, controlling release kinetics, and potentially combining multiple mechanisms of action to overcome pathway complexity.
2Stability of the object's composition
If crystalline forms of CD73 inhibitors are developed, then pharmaceutical composition stability is improved, but manufacturing and characterization complexity increases
Solution Approach 1:
The patent applies preliminary action by pre-characterizing multiple crystalline forms and selecting the most stable and manufacturable polymorph for development. By conducting thorough stability, solubility, and processing studies on different crystal forms before clinical development, the team identifies optimal candidates that balance stability requirements with manufacturing feasibility, avoiding later formulation problems.
Solution Approach 2:
The patent uses crystalline forms as intermediary structures that mediate between the molecular-level drug substance and the macroscopic pharmaceutical formulation. Different crystal packings serve as intermediaries with distinct properties, allowing optimization of both stability and manufacturability through selection of appropriate crystal forms without changing the active pharmaceutical ingredient itself.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The crystalline forms of 5-[5-[2-isopropylcyclopropyl]-6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione effectively inhibit CD73 activity, enhancing antitumor immunity and providing a therapeutic option for various types of cancer, including those resistant to other treatments.
Implementation Method 1
CD73, also known as 5'-nucleotidase or ecto-5'nucleotidase (EC 3.1.3.5), is an enzyme that converts 5' mononucleotides to nucleosides
Implementation Method 2
a peak in the X-ray diffraction pattern, at a diffraction angle 2-theta of 4.7°
Implementation Method 3
a peak in the X-ray diffraction pattern, at a diffraction angle 2-theta of 4.7°
Data Source
AI summary
The present invention relates to crystalline forms of 5-[5-[2-isopropylcyclopropyl] -6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione, and pharmaceutical compositions comprising them, which inhibit the activity of CD73 and are useful for treating cancer.