Selective Arginase Inhibition to Preserve T-Cell Responsiveness
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Solution Overview
Problem
Tumors evade the immune system by reducing L-arginine levels through increased arginase expression, leading to immune suppression, which existing treatments have not effectively addressed.
Innovation Solution
Development of arginase inhibitors, such as compounds of formula (Ib), (II), (III), (IVb), (Vc), (VI), (VII), and (VIIIb), or their pharmaceutically acceptable salts, to inhibit arginase activity and restore immune function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If arginase expression is increased to remove ammonia through urea synthesis, then ammonia removal efficiency is improved, but L-arginine levels decrease leading to immune suppression
Solution Approach 1:
The patent applies parameter changes by developing selective arginase inhibitors that modulate arginase activity. The inhibitors change the functional parameters of arginase to reduce its catalytic activity, thereby preventing excessive conversion of L-arginine to urea. This maintains L-arginine levels while preserving ammonia removal capability through regulated arginase function.
Solution Approach 2:
The patent introduces arginase inhibitors as intermediary substances that mediate between arginase activity and L-arginine levels. These inhibitors act as regulatory intermediaries that control the enzyme-substrate interaction, preventing direct depletion of L-arginine while allowing controlled ammonia metabolism.
2Productivity
If arginase activity is increased to produce ornithine for cell proliferation, then cell proliferation is improved, but L-arginine levels decrease leading to impaired T-cell responsiveness
Solution Approach 1:
The patent uses parameter changes by selectively inhibiting arginase activity to regulate the balance between ornithine production and L-arginine availability. The inhibitors modify enzymatic parameters to prevent excessive L-arginine consumption, thereby maintaining T-cell responsiveness while allowing controlled cell proliferation through ornithine synthesis.
Solution Approach 2:
The patent applies partial action by using selective arginase inhibitors that provide just enough inhibition to maintain L-arginine levels for immune function, rather than complete inhibition. This partial inhibition allows sufficient ornithine production for cell proliferation while preventing excessive L-arginine depletion that would impair T-cell responsiveness.
3Productivity
If circulating arginase levels are increased to remove ammonia, then ammonia removal is improved, but immune cells experience L-arginine depletion and functional suppression
Solution Approach 1:
The patent introduces arginase inhibitors as intermediary substances that mediate the conflict between ammonia removal and immune function. These inhibitors regulate the harmful effect of arginase overactivity by controlling the conversion of L-arginine to urea, thereby preventing immune cell L-arginine depletion while maintaining ammonia clearance capability.
Solution Approach 2:
The patent converts the harmful effect of arginase overactivity (L-arginine depletion causing immune suppression) into a beneficial regulated state. The inhibitors transform excessive arginase activity into controlled activity, turning the harmful depletion effect into a balanced metabolic function that supports both ammonia removal and immune health.
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 arginase inhibitors reverse immune suppression, reactivating anti-cancer immunity and potentially treating cancers like renal cell carcinoma, lung cancer, and respiratory inflammatory diseases like COPD and asthma.
Implementation Method 1
Arginase is a manganese metalloenzyme that catalyzes the conversion of L-arginine to urea and L-ornithine. Pharmacologic inhibition of arginase activity has been shown to reverse the low L-arginine induced immune suppression in animal models.
Data Source
AI summary
Disclosed are compounds of formula (Ib) or (Vc), or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising compounds of formula (Ib) or (Vc) and methods of using the same for treating cancer, respiratory inflammatory disease, and inhibiting arginase; wherein R1 is —H or —C(O)CH(R1a)NHR1b; and R1a is selected from —H, —(C1-C4) alkyl and CH2OR1c; R1b is —H; or alternatively, R1a and R1b, together with the atom to which they are attached, form a 5-membered heterocyclic ring; and R1c is H or —CH3.