Virtual ICH M7 Expert Review Workshop Dr. Sian Ives Sales Manager - PowerPoint PPT Presentation

Review the statistical prediction ? Expert Review M7 classification • No hypothesis is identified • The relevant nearest neighbours are all positive and fire Derek alert 027 • Negative nearest neighbours are dissimilar and are not alkylating agents.

Expert review ? • Positive prediction • No reason to doubt. • Equivocal prediction • No hypothesis identified • Relevant nearest neighbours in the training set are positive Expert • Nearest neighbours that are negative are dissimilar and are not Review alkylating agents. M7 classification

Please make your selection 1. Class 3 – Alerting structure 2. Class 5 – No alerts or alerting with sufficient data to demonstrate lack of mutagenicity 3. Unsure

M7 Classification – 5689-83-8 ? Classification • Derek Nexus Expert Review • No reason to doubt Derek Nexus positive prediction (alert 027) • Sarah Nexus M7 • Equivocal prediction overruled as relevant classification examples are positive

M7 Classification – 5689-83-8 ? Expert Review Class 3 Alerting structure M7 classification

Example 5

Review high level predictions ? Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification • Negative prediction • No misclassified or unclassified features.

Review the statistical prediction ? Expert Review M7 classification No hypothesis is identified. Activity of nearest neighbours is associated with their ability to act as alkylating agents or the epoxide, neither are relevant to the query.

Review the statistical prediction ? Expert Review M7 classification No hypothesis is identified. Parent alcohol and sulfonic acid are both negative examples in the training set.

Expert review ? • Negative prediction • No misclassified or unclassified features. • Equivocal prediction • No hypothesis identified • Activity of nearest neighbours is associated with structural features Expert enabling them as alkylating agents Review • Parent alcohol and sulfonic acid are negative examples in the training set. M7 classification

Please make your selection 1. Class 3 – Alerting structure 2. Class 5 – No alerts or alerting with sufficient data to demonstrate lack of mutagenicity 3. Unsure

M7 Classification – Example 5 ? Compound • Derek Nexus • Inactive prediction with no misclassified or Expert unclassified features. Review • Sarah Nexus • Equivocal prediction overruled as positive examples M7 are not relevant and parent compounds are negative classification examples in the training set.

M7 Classification – Example 5 ? Compound Expert Review Class 5 Class 5 - No alerts or alerting with sufficient data to demonstrate lack of mutagenicity M7 classification

Example 6

Review high level predictions ? Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification Alert 315: Acid halide Sulphonyl chloride functional group match sulphonyl halide toxicophore III However risk of false positives flagged in Ames tests in DMSO . [Amberg A et al., Organic Process Research and Development (2015), 19(11), 1495-1506] 5-strain Ames negative results for Benzene sulphonyl chloride (98-09-9) in acetonitrile.

Additional information (from literature) ? Expert Review Amberg et al., Organic Process Research and Development (2015), 19(11), 1495-1506 M7 classification

Additional information (From Vitic) No Ames data available on 15945-07-0 2,4,5-Trichlorobenzenesulfonyl chloride ? 5-strain Ames negative results for Benzene sulphonyl chloride (98-09-9) in acetonitrile. [Amberg A et al., Organic Process Research and Development (2015), Expert 19(11), 1495-1506] Review (false positives due to reactivity with DMSO discarded). M7 classification

Review the statistical prediction ? Expert Review Compounds 1 and 7 confirmed absence of activity of benzene with chloro substituents. M7 classification Compounds from training set are dissimilar to the test compound. i.e., none of the examples contain a sulphonyl chloride group.

Expert review • Predicted positive ? • Fires alert 315 for acid halide, however Ames positive calls challenged as potential for false positives due to reactivity with DMSO • 5-strain Ames negative results for similar compound benzene sulphonyl chloride (98-09-9) in acetonitrile. Expert Review • Inactive prediction M7 • Nearest neighbours from Sarah training dissimilar to classification the test compound i.e. no sulfonyl chloride group.

Please make your selection 1. Class 3 – Alerting structure 2. Class 5 – No alerts or alerting with sufficient data to demonstrate lack of mutagenicity 3. Unsure

M7 Classification – Example 6 ? Classification • Derek positive prediction (alert 315) • Compound may react with DMSO to produce a reactive, Expert mutagenic intermediate Review • The alert fires to explain artefactual activity that may be seen • Similar compounds Ames negative in other solvents. • Sarah negative prediction M7 • Nearest neighbours from Sarah training dissimilar to the test classification compound i.e. no sulfonyl chloride group • Similar compound in the training set, benzene sulphonyl chloride (98-09-9) is negative. • Overrule Derek prediction

M7 Classification – Example 6 ? Expert Review Class 5 M7 No alerts or alerting with sufficient data to demonstrate lack of mutagenicity classification

Example 7

Review high level predictions ? Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification Most training set examples have an aromatic group attached to the alkene (C3 position) which Derek Nexus has described as having decreased mutagenic activity.

Review the statistical prediction ? Expert Review M7 classification • There is no protocol information.

Expert review ? • Plausible prediction • Fires alert 664 for alpha,beta-unsaturated compounds • Mutagenicity related to electronegativity and steric hindrance around the double bond • Aryl substituents at C3 are typically negative or reduced mutagenicity. Expert Review • Negative prediction • Negative compounds mostly have an aryl substituent at C3 position M7 • Most similar compound, 30418-35-2 is negative however there is classification no protocol information.

Please make your selection 1. Class 3 – Alerting structure 2. Class 5 – No alerts or alerting with sufficient data to demonstrate lack of mutagenicity 3. Unsure

M7 Classification – Example 7 ? • Predicted positive • No data to support overturning the prediction. Expert Review • Predicted inactive M7 • Many of the supporting examples are not relevant. classification

M7 Classification – Example 7 ? Expert Review Class 3 Alerting structure M7 classification

Example 8 Compound

Review high level predictions ? Compound Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification

Review the expert prediction • Candidate for alert 351 • Phenyl substitution of secondary amine excluded and electron withdrawing group present on the aromatic ring deactivating ? • Primary amine group does not activate due to ortho aromatic amine substitution which may cause steric hindrance. Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification 351

Review the statistical prediction ? Expert Review M7 classification Good strain data for both negatives

Expert review • Negative with no misclassified or unclassified features ? • Near miss of alert 351 • Exclusion based on limitations in substitution allowed on second amine group in ortho diamines • Exclusion based on available evidence rather than negative data. • Sarah Nexus identifies a positive hypothesis for aromatic amine Expert Review which is overruled by nearest neighbours • Two negative nearest neighbours are relevant and electronically similar to both amines present in query structure M7 • Data lacking for ortho-substituted aromatic amine and there is a classification data gap for this sub-class.

Please make your selection 1. Class 3 – Alerting structure 2. Class 5 – No alerts or alerting with sufficient data to demonstrate lack of mutagenicity 3. Unsure

M7 Classification – Example 8 Compound ? • Derek inactive prediction • Exclusion from alert 351 based on steric hindrance around aromatic amine • Query compound may adopt a conformation with less steric hindrance and potential to intercalate. Expert Review • Sarah negative prediction • Two most similar relevant examples negative • No data for this type of ortho substitution relating to M7 steric influence. classification • While there is limited data available relating to this type of ortho substitution of an aromatic amine, the same substitution in the para position gave negative results. No need to overturn Derek Nexus and Sarah Nexus.

M7 Classification – Example 8 ? Compound Expert Review Class 5 No alerts or alerting with sufficient data to demonstrate lack of M7 classification mutagenicity

Example 9

Review high level predictions ? Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification • Equivocal prediction • Training set examples are not relevant to query • Check additional information…

Review the statistical prediction ? Expert Review M7 classification • Close match with training set compound • Ames positive with results in two strains • No reason to doubt the positive.