Selective SRC Kinase Inhibitors With Reduced ABL Off-Target Toxicity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current tyrosine kinase inhibitors, such as dasatinib and bosutinib, suffer from off-target activities leading to side effects like cardiotoxicity, immunosuppression, and pro-oncogenic effects, limiting their therapeutic efficacy in treating cancers like breast cancer and colorectal cancer, despite their validated etiological role in SRC kinase activity.
Innovation Solution
Development of pyrazolopyrimidine compounds that selectively inhibit SRC kinase and its family members, including LYN, FYN, LCK, HCK, FGR, BLK, and FRK, with improved selectivity over ABL kinase, reducing off-target effects and enhancing safety and efficacy in treating cancers and SRC-associated disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dual ABL/SRC kinase inhibitors (dasatinib, bosutinib) are used to treat cancer, then SRC kinase activity is inhibited, but off-target activities cause cardiotoxicity, immunosuppression, and pro-oncogenic effects
Solution Approach 1:
The patent applies local quality by designing a kinase inhibitor with selective binding properties targeting specific kinase isoforms (SRC, LYN, FYN, LCK, HCK, FGR, BLK, FRK, YES) while avoiding ABL kinase. The compound achieves differentiated interaction with specific kinase active sites through its molecular structure, providing selective inhibition without broad off-target effects that cause cardiotoxicity and immunosuppression
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure parameters of kinase inhibitors to achieve selective binding. The compound of formula (I) with specific substituent patterns (R1-R11 groups) alters the molecular parameters to preferentially bind to SRC family kinases over ABL kinase, thereby changing the selectivity profile and reducing off-target toxicities
2Reliability
If ABL kinase inhibitors are used to treat cancer, then SRC kinase activity is inhibited, but ABL signaling exerts an anti-oncogenic role in some cancers
Solution Approach 1:
The patent applies local quality by creating a kinase inhibitor with selective binding properties targeting specific kinase isoforms (SRC, LYN, FYN, LCK, HCK, FGR, BLK, FRK, YES) while avoiding ABL kinase. The compound achieves differentiated interaction with specific kinase active sites through its molecular structure, providing selective inhibition without broad off-target effects that cause cardiotoxicity and immunosuppression
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure parameters of kinase inhibitors to achieve selective binding. The compound of formula (I) with specific substituent patterns (R1-R11 groups) alters the molecular parameters to preferentially bind to SRC family kinases over ABL kinase, thereby changing the selectivity profile and reducing off-target toxicities
3Reliability
If KIT kinase activity is inhibited by dasatinib and bosutinib, then SRC kinase activity is inhibited, but myelosuppression occurs affecting immune defense
Solution Approach 1:
The patent applies local quality by designing a kinase inhibitor with selective binding properties targeting specific kinase isoforms (SRC, LYN, FYN, LCK, HCK, FGR, BLK, FRK, YES) while avoiding ABL kinase. The compound achieves differentiated interaction with specific kinase active sites through its molecular structure, providing selective inhibition without broad off-target effects that cause cardiotoxicity and immunosuppression
Data Source
Figure 1
Figure 2
Figure 3
AI summary
The disclosure relates to a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, wherein: R1 is selected from a group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl; R2 is selected from a group consisting of H, halo, OR11, NHR11, alkyl, alkenyl and alkynyl; R3 is selected from a group consisting of alkyl, alkenyl, alkynyl, aryl, halo, aryloxy, NHCO2R4, NHCONR5R6, NHCOR7, NH-alkyl, NH-alkenyl, NH(CH2)n-aryl, (CH2)p-heteroaryl, (CH2)qCO2R8, (CH2)rCOR9 and NHSO2R10, wherein each alkyl, alkenyl, aryl or heteroaryl moiety in the aforementioned list is optionally further substituted by one or more groups selected from alkyl, halo, OH, NH2, alkoxy, aryloxy, alkylamino, arylamino, carboxyl and carboxamide; R4 to R11 are each independently selected from a group consisting of alkyl, alkenyl and aryl; and n is selected from a group consisting of 0, 1, 2, 3, 4, 5 and 6, p is selected from a group consisting of 0, 1, 2, 3, 4, 5 and 6, q is selected from a group consisting of 0, 1, 2, 3, 4, 5 and 6, and r is selected from a group consisting of 0, 1, 2, 3, 4, 5 and 6. The disclosure also relates to pharmaceutical compositions, therapeutic uses and process for preparing the compound of the disclosure.