CBP/p300 Bromodomain and KRAS Inhibitor Combination for Resistance
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Solution Overview
Problem
Current KRAS inhibitors exhibit decreased efficacy over time and resistance when used as single agents or in combination therapies for treating cancers with KRAS mutations, necessitating the development of combination strategies that provide deeper and longer-lasting responses.
Innovation Solution
Combining a CBP/p300 bromodomain inhibitor with a KRAS inhibitor, where the bromodomain inhibitor selectively binds to CBP/p300, enhances therapeutic efficacy and prevents resistance, particularly in cancers with KRAS oncogenic alterations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a KRAS inhibitor is used as a single agent, then initial therapeutic effect is achieved, but efficacy decreases over time due to resistance
Solution Approach 1:
The patent combines a KRAS inhibitor with a CBP/p300 bromodomain inhibitor to create a dual-mechanism therapy. The KRAS inhibitor blocks oncogenic KRAS signaling, while the CBP/p300 bromodomain inhibitor targets epigenetic modifications, preventing cancer cell adaptation and resistance development, thereby maintaining therapeutic efficacy over time
Solution Approach 2:
The CBP/p300 bromodomain inhibitor acts as an intermediary that modulates gene expression programs downstream of KRAS signaling. By targeting bromodomain-containing proteins that read epigenetic marks, it interferes with the transcriptional reprogramming that cancer cells use to overcome KRAS inhibitor resistance
2Reliability
If combination therapies are used to overcome resistance, then therapeutic depth increases, but treatment complexity increases
Solution Approach 1:
The patent merges two targeted therapies with complementary mechanisms of action: KRAS inhibition and CBP/p300 bromodomain inhibition. This combination addresses both the primary oncogenic driver and the adaptive resistance mechanisms, achieving deeper therapeutic responses while maintaining a focused targeted therapy approach rather than escalating to complex chemotherapy regimens
Data Source
AI summary
The present invention is inter alia concerned with (i) a combination of a CBP/p300 bromodomain inhibitor and a KRAS inhibitor for use in the treatment of a patient suffering from cancer, wherein the cancer exhibits an oncogenic alteration in the KRAS; (ii) a kit comprising (a) a pharmaceutical dosage form comprising a CBP/p300 bromodomain inhibitor and (b) a pharmaceutical dosage form comprising a KRAS inhibitor, and (iii) a pharmaceutical dosage form comprising a CBP/p300 bromodomain inhibitor and a KRAS inhibitor.