Invited final application for an amr centre project (стр. 2 )

Q10	Target Biology Tractability: Please provide brief details on the following (no more than Ѕ page per question)
(a)	Description of the target

Unknown novel target (no known function) novel target target inferred from phenotypic data known drug target / family other

(b)	Validation that the therapeutic approach or target is relevant to human disease?

Hypothetical genetic or proteomic in vitro studies

in vivo animal model exploratory clinical studies registrational clinical studies

(c)	Please describe the biological assays available, their duration and throughput

No assays primary assay (functional/high content) selectivity assays in vivo model other

(d)	Please explain the translation between assays, in vivo models, and activity in a human context.

(e)	Please outline the ORDER in which the biological assays will be applied to the progression of compounds i. e. what is the ‘screening cascade’ that will be used, what criteria would select a compound for further study at each step? Which assay, or assays, is, or are, considered to be key and discriminating?

(f)	Please outline any structural or computational biology known about the target (eg, X-ray structure, binding site prediction, domain analysis, sequence comparisons).

(g)	What are the known or potential mechanism-related side effects in animals and man of modulating this target?

Unknown hypothetical predictable based on data demonstrated other

(h)	What are the potential safety considerations due to likely off-target activities?

Unknown hypothetical predictable based on data demonstrated other

	Chemistry Tractability:
Q11 (a)	Please give 1-2 archetypal structures for the most promising members of the active chemical series being exploited. .
	1st archetypal structure	2nd archetypal structure

(To paste structures in the boxes above, please select ‘unprotect’ from the Tools menu. Reprotect for forms afterwards to allow the remaining form fields to be completed easily)

Please describe the starting points that apply to the compounds / series you have shown above:

natural ligand research tool existing licensed drug

drug-like compound reported in the patent literature

a drug-like compound reported in peer reviewed literature

virtual screen with pharmacophore / homology model based on X-ray / crystal structure

proprietary drug-like hit / lead

(b)	What is the proposed clinical route of administration?
	topical intravenous subcutaneous/parental inhaled oral other/ unknown

(c)	Please indicate the range of activity in the primary assay; activity in a secondary / cellular assay; activity in any selectivity or promiscuity assay; number of compounds tested in each structural series and main SAR to date. See Tables in Appendix 1

(d)	Please indicate the following: the range of molecular weight; ligand efficiency (LE), clogP, PSA; and any available physicochemical / ADME data eg. aqueous solubility; microsomal stability data; plasma protein binding; permeation measurements; efflux measurements; CYP450 inhibition; hERG binding. See Tables in Appendix 1

(e)	What is the evidence for these compounds binding to the desired target? Please outline the technique (X-ray crystallography, NMR, DSC, SPR, covalent linkage etc.) and the results. See Tables in Appendix 1

(f)	Summarise the key challenges to optimization of the series towards the target profile and why these are the important values.
(g)	Please indicate any measured in vivo ADME parameters in a rodent species including (if applicable) : Plasma clearance; %F bioavailability; i. v. plasma half-life. See Tables in Appendix 1

(h)	Please indicate any measured ADME parameters in a non-rodent species including (if applicable): Plasma clearance; %F bioavailability; i. v. plasma half-life. See Tables in Appendix 1

(i)	Is there consistency in the in vitro metabolism rates across non-clinical species and man? Are in vitro metabolism profiles similar, if known?

(j)	Has any assessment (computational or experimental) of structural liability for reactive metabolites, genotoxicity or phospholipidosis been carried out? If so, please give details.

(k)	Has any general broad target enzyme, ion-channel or receptor screening been carried out? Please give details of any binding observed. See Tables in Appendix 1

(l)	Please detail any overt physical signs observed during in vivo studies performed to date

(m)	The table above is intended to summarise the known data for the lead series. Please outline the medicinal chemistry strategy for the respective series that addresses the issues detailed in f) above and how it will deliver the Candidate Profile (This explanation may be given in an Appendix if desired)

Q12	Translation or Clinical Tractability: Please provide brief details on the following (no more than Ѕ page per question except for (c) where 1 page is allowed; additional information may be provided in an Appendix). )
(a)	Please describe in detail the precise target patient population and any known subsets of these patients

(b)	Please describe how patients will be selected for treatment. Is there a current or potential need for a diagnostic to stratify patients?

(c)	Please outline the anticipated study design for Proof of Concept (for novel mechanisms) or Proof of Efficacy (for known mechanisms). Please estimate the dosing duration of these Phase 2 studies

(d)	Please describe the comparator, if any, to be used in the studies in patients. Will the new agent be dosed alone, in addition to any comparator or in combination with other agents? What drug-drug interactions are likely to be important?

(e)	What are the maximum acceptable, and the ideal, dosing frequency for clinical use? (The frequency of dosing may be a consequence of competition, compliance or likely co-medication.)

Maximum 1x 2x 3x 4x daily Other / unknown at this time Ideal 1x 2x 3x 4x daily Other / unknown at this time

(f)	Is there an identified, measurable and validated biomarker for clinical efficacy in man? Is there a potential pharmacodynamics biomarker or imaging method? Does any biomarker measure target engagement in the desired tissue?
	Activity and PD biomarker known Effect biomarker only Potential suggested None identified

Q13	PROJECT PLAN (Optional)

Please outline the forward plan of investigation proposed to be funded by the Trust including: