CD206 Modulators Reprogramming M2 Macrophages for Pancreatic Cancer

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Solution Overview

Problem

Pancreatic cancer has a poor prognosis due to rapid progression and limited efficacy of current treatments, with immunotherapy showing limited success in 'cold' tumors characterized by a lack of cytotoxic T cells and an immune-evasive microenvironment, where CD206high M2 macrophages promote tumor growth and metastasis.

Innovation Solution

Development of small molecule modulators targeting the CD206 receptor to reprogram M2 macrophages into a M1 phenotype, thereby enhancing anti-tumor immunity, which involves specific compounds of Formula I, II, and III that selectively target and modulate CD206-positive tumor-associated macrophages.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If immunotherapy is used to treat pancreatic cancer, then anti-tumor immunity is enhanced, but the therapy shows limited efficacy in 'cold' tumors with immune-evasive microenvironments

Engineering Contradiction:

Improveefficacy of immunotherapyVSAvoidimmune-evasive microenvironment

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent uses CD206 as an intermediary target to indirectly modulate the immune microenvironment. By targeting CD206 on M2 macrophages with small molecule modulators, the therapy converts the immune-evasive microenvironment into an immune-active one, enabling T cell infiltration and function without directly targeting T cells themselves.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the phenotypic parameters of tumor-associated macrophages by shifting them from M2 (immunosuppressive) to M1 (immunostimulatory) state. This parameter change in macrophage polarization fundamentally alters the microenvironment properties, transforming it from immune-evasive to immune-permissive.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If M2 macrophages are present in the tumor microenvironment, then tumor growth and metastasis are promoted, but reprogramming them to M1 phenotype is needed to enhance anti-tumor immunity

Engineering Contradiction:

Improveanti-tumor immunityVSAvoidtumor-promoting activity of M2 macrophages

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

Instead of directly targeting and eliminating M2 macrophages or attacking tumor cells, the invention inverts the approach by reprogramming M2 macrophages into M1 phenotype. This converts the harmful immune suppressive cells into beneficial immune activators that promote anti-tumor immunity.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent induces a phenotypic parameter change in macrophages from M2 to M1 state through small molecule modulation of CD206. This parameter change transforms the functional properties of these cells from tumor-promoting to tumor-fighting.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If small molecule modulators are developed to target CD206, then M2 macrophages can be reprogrammed to M1 phenotype, but the complexity of drug development and clinical translation increases

Engineering Contradiction:

Improvemacrophage reprogramming efficacyVSAvoidcomplexity of drug development

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention extracts and targets a specific receptor (CD206) that is highly expressed on M2 macrophages but not on M1 macrophages or other cell types. This selective targeting simplifies the therapeutic approach by focusing on a single key molecule that controls macrophage polarization, rather than attempting to modulate multiple immune pathways simultaneously.

Inventive Principle:

Principle #2Taking out (Extraction)

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 compounds effectively reprogram M2 macrophages into M1 macrophages, inducing phagocytosis, autophagy, and apoptosis in tumor cells, leading to tumor regression and improved survival rates by altering the tumor microenvironment.

Implementation Method 1

Ligand binding or low pH induces 'rolling-in' (via multiple Ca+-dependent intramolecular interactions between the carbohydrate recognition domains) and the closed ('active') form of the receptor

Methodology Applied

Scientific EffectLigand binding:

Implementation Method 2

CD206 via its eight carbohydrate recognition domains is involved in recognition and binding of mannan and fucose carbohydrate residues from microbial organisms, or via its fibronectin domain II as a scavenger receptor in the phagocytosis of collagen fragments

Methodology Applied

Scientific EffectPhagocytosis:

Implementation Method 3

triggers in M2 macrophages, among other signaling cascades, via GRB2-mediated activation of small Rho-GTPases NF-kB signaling activation and induction of phagocytosis and autophagy

Methodology Applied

Scientific EffectAutophagy:

Data Source

PatentUS20230056497A1CD206 Modulators Their Use and Methods for Preparation

Publication Date: 2023.02.23 THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY DEPARTMENT OF HEALTH & HUMAN SERVICES

AI summary

Compounds of Formula I, Formula II, and Formula III and the pharmaceutically acceptable salts thereof are disclosed. The variables X, a, b, c, d, R1-4, R10-15 and R17-22 are disclosed herein. The compounds are useful for treating cancer disorders, especially those involving M2 phenotype of macrophages. Pharmaceutical compositions containing compounds of Formula I or Formula II or Formula III and methods of treatment comprising administering compounds of Formula I and Formula II and Formula III are also disclosed.