SMO Modulator Compounds for Resistant Basal Cell Carcinoma
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Solution Overview
Problem
Current SMO antagonists have limited efficacy due to rapid development of resistance, particularly in basal cell carcinoma, and they often cause adverse effects, leading to high discontinuation rates.
Innovation Solution
Development of novel compounds that act as Smoothened (SMO) receptor antagonists, capable of targeting multiple clinically relevant SMO mutations, to effectively inhibit the Hedgehog signaling pathway.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current SMO antagonists are used to treat basal cell carcinoma, then initial therapeutic effect is achieved, but resistance develops rapidly leading to treatment failure
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of SMO antagonists through various substituents and molecular configurations (as shown in the general formulas and specific examples). These structural parameter changes create novel compounds with improved binding affinity and resistance to mutations, thereby extending the duration of therapeutic response while maintaining initial efficacy.
2Reliability
If current SMO antagonists are administered at standard doses, then therapeutic effect is achieved, but adverse effects occur leading to high discontinuation rates
Solution Approach 1:
The patent applies local quality by introducing specific substituents at particular positions on the SMO antagonist molecular structure (as depicted in the general formulas with R1-R6 variables). This localized modification optimizes the drug's interaction with the SMO receptor while reducing off-target effects, thereby maintaining therapeutic efficacy while minimizing adverse effects such as muscle spasms, alopecia, and dysgeusia.
3Reliability
If SMO antagonists target wild-type SMO, then initial response is achieved, but mutations in SMO lead to resistance
Solution Approach 1:
The patent applies universality by designing SMO antagonist compounds with molecular structures that can bind to multiple variants of the SMO receptor, including both wild-type and mutated forms (as shown in the general formulas and specific examples). This multi-functional design allows the compounds to maintain activity across different SMO genetic backgrounds, thereby overcoming resistance while preserving initial response rates.
Data Source
AI summary
The disclosures herein relate to novel compounds of Formula (1a) or a salt thereof, wherein X1, X2, X3, X4, Y1, Y2, Y3, Y4, Z1, Z2, Z3, Z4, W, R1, R4, R5, R6 and R7 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with SMO receptors.