Saturated PBD Dimer Linkers for Selective DNA Binding
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Solution Overview
Problem
Pyrrolobenzodiazepine (PBD) dimers with endo- or exo-unsaturation in the C-ring have limitations due to high reactivity with cellular thiol-containing molecules, leading to poor tumour selectivity and drug uptake, which affects their antitumor activity.
Innovation Solution
Development of PBD dimer drug linkers and conjugates without endo- or exo-unsaturation in the C-ring, allowing for ready conjugation to ligand units like antibodies, enhancing DNA-binding affinity and cytotoxicity while reducing reactivity with cellular nucleophiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PBD dimers with endo- or exo-unsaturation in the C-ring are used, then DNA-binding affinity and cytotoxicity are enhanced, but reactivity with cellular thiol-containing molecules increases leading to poor tumour selectivity and drug uptake
Solution Approach 1:
The patent applies parameter changes by modifying the saturation state of the C-ring in PBD dimers. Specifically, it transitions from endo- or exo-unsaturated C-rings (which have high reactivity) to a saturated C-ring configuration (as seen in compounds like DSB-120 and SG2000). This structural parameter change reduces reactivity with cellular thiol-containing molecules while maintaining DNA-binding affinity and cytotoxicity, thereby resolving the contradiction between reliability and harmful reactivity.
2Reliability
If PBD dimers with high reactivity are used, then cytotoxicity is enhanced, but tumour selectivity and drug uptake decrease
Solution Approach 1:
The patent modifies the chemical structure parameter of the C-ring from unsaturated to saturated configuration. This parameter change reduces the reactivity of the PBD dimer with cellular nucleophiles, thereby improving tumour selectivity and drug uptake characteristics while preserving the desired cytotoxicity against tumour cells.
3Manufacturing precision
If PBD dimers are conjugated to ligand units, then tumour selectivity is improved, but device complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the PBD dimer structure into distinct functional modules: the PBD dimer core (with saturated C-ring), the linker region, and the ligand unit. This modular segmentation allows for systematic conjugation to various ligands (such as antibodies) to achieve tumour selectivity while managing structural complexity through standardized connection points and methodologies.
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 PBD dimer drug linkers and conjugates exhibit high tolerability and therapeutic index, making them promising candidates for clinical development with improved cytotoxicity and tumour selectivity.
Implementation Method 1
Pyrrolobenzodiazepines (PBDs) have the ability to recognise and bond to specific sequences of DNA
Implementation Method 2
PBDs are of the general structure... which provides them with a right-handed twist when viewed from the C ring towards the A ring. This gives them the appropriate three-dimensional shape for isohelicity with the minor groove of B-form DNA, leading to a snug fit at the binding site
Implementation Method 3
In the B-ring there is either an imine (N=C), a carbinolamine (NH-CH(OH)), or a carbinolamine methyl ether (NH-CH(OMe)) arm at the N10-C11 position which is the electrophilic centre responsible for alkylating DNA
Implementation Method 4
The PBD dimers are thought to form sequence-selective DNA lesions such as the palindromic 5'-Pu-GATC-Py-3' interstrand cross-link which is thought to be mainly responsible for their biological activity
Data Source
AI summary
A compound of formula I and salts and solvates thereof, wherein: R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo; where R and R' are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo; R" is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NRN2 (where RN2 is H or C1-4 alkyl), and/or aromatic rings, e.g. benzene or pyridine; Y and Y' are selected from O, S, or NH; R6, R7, R9 are selected from the same groups as R6, R7 and R9 respectively; R11b is selected from OH, ORA, where RA is C1-4 alkyl; and RL is a linker for connection to a cell binding agent.