Synthetic libraries Natural Product libraries Re-purposing of old drugs

1. Synthetic libraries • Natural Product libraries • Re-purposing of old drugs Target ID Supporting Data Clustering & Synthesis TBD-UK drug discovery and development blueprint Genomic Based Approach Phenotypic Approach 1) Target ID & Validation 3) Assay development 4) HTS (>60% inhibition), virtual & fragment screening 5) Ligand optimisation (IC50 <100 nM) PREFERRED M. tuberculosis H37Rv HIT identification • MIC in macrophage model • MSC/Activity in persistence models • MIC against resistance panel • Cidal or static activity • Frequency of resistance mutation • Synergism, antagonism or additive action • MIC vsE. coli, S. aureus, C. albicans & • M. smegmatis, M. aurum, BCG 1) MIC >90% inhibition at 30 mMMABA/SPOT TEST/break point = HIT 2) MIC < 5 mM MABA & cytotox counter screen (eg HepG2, VERO, HeLa, HS27) IC50/MIC >10 MEET CRITERIA = PROGRESS. FAIL = RE-SYNTHESIS /SELECTION LEAD optimisation 3) MIC <1 mM H37Rv & 10% serum/4% albumin PREFERRED 4) No rat hepatocytetox & reactive metabolite formation ESSENTIAL 5) GI, microsome & plasma stability ESSENTIAL 6) IC50 >10 mM Cyp450 (2C9, 2C19 & 3A4) PREFERRED 7) Good permeability (oral) in CaCo2 model PREFERRED 8) hERG = No issues ESSENTIAL 9) LogP <5, MWt <450 & solubility >10mg/ml, Protein binding <90%, polar surface area <140 A2, rotatable bonds <10, H-bonds <12 PREFERRED Acute Mouse Model (Selection based on all data) • Resistant mutant genome sequence • Cosmid libraries • MIC vs over/under expressing strain • RT-PCR 10) PK, acute/chronic toxicity & efficacy established 11) Safety margins demonstrated in Rat and Dog MEET CRITERIA = PROGRESS. FAIL = RE-OPTIMISE or RE-CONSIDER SERIES Pre-clinical Development Clinical Development 12) Activity in combination(s) with other TB agents • Biomarkers • Mathematical models • PET-CT imaging