Cross-Indication Validation · 3 Therapeutic Areas · 28 Targets

Discovery Sprints Dashboard

Three independent discovery sprints across oncology, neurodegeneration, and immunology. 28 targets analyzed through the V5 engine to validate cross-indication discrimination, modality separation, and state-dependent behavior.

Cross-Indication Comparison

METRIC
Targets	9	10	9
Pursue	2	6	5
No-Go	4	2	2
State-Dependent	2	0	0
Borderline	1	2	2
Mean Score	45.4	58.0	74.7
Highest	94	91	95
Lowest	0	0	22

Oncology

9 Targets · 18 Structures

Hard-target panel: transcription factors, IDPs, and emerging targets

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Neurodegeneration

9 Targets · 10 Analyses

Kinases, proteases, IDPs, and aggregation-prone proteins

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Immunology

9 Targets · Modality Discrimination

Kinases, checkpoint proteins, cytokines, and cell-surface antigens

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AREA:CLASS:

All Targets (28)

			%ILE		MODALITY	KEY FINDING
JAK1JAK1 6N7A (A)	Immun	95	100th	PURSUE	Traditional SM	Highest score across all sprints — tofacitinib approved
RB1 Pocket DomainRB1 3POM, 1N4M	Oncol	94	95th–100th	PURSUE	Traditional SM	Highest score in panel but loss-of-function biology
PD-L1CD274 5J89 (A)	Immun	93	97th	PURSUE	Traditional SM	SM PD-L1 inhibitors in clinical trials (BMS)
LRRK2 KinaseLRRK2 7LI4 (A)	Neuro	91	98th	PURSUE	Traditional SM	Validated kinase, multiple clinical candidates
BTKBTK 5P9J (A)	Immun	88	97th	PURSUE	Traditional SM	Validated kinase — ibrutinib/acalabrutinib approved
KEAP1 Kelch DomainKEAP1 4IFL, 4L7B	Oncol	86	92nd–95th	PURSUE	Traditional SM	Consistent across states, 312 Da lead, 5/5 coherence
CTLA-4CTLA4 3OSK	Immun	83	92nd	BORDERLINE	Biologic Only	Structurally druggable but biologics-only modality
GSK3-betaGSK3B 1Q5K (A)	Neuro	82	92nd	PURSUE	Traditional SM	Validated kinase, tideglusib in trials
TYK2TYK2 6NZP (A)	Immun	82	92nd	PURSUE	Traditional SM	Deucravacitinib (Sotyktu) approved 2022
AChEACHE 4EY7 (A)	Neuro	80	90th	PURSUE	Traditional SM	Approved drugs exist (donepezil, rivastigmine)
STAT3 SH2STAT3 6NUQ, 1BG1	Oncol	78	80th–87th	BORDERLINE	Traditional SM	Historically difficult — decades without approved SM drugs
TDP-43 RRM1TARDBP 4BS2 (A)	Neuro	76	85th	PURSUE	Traditional SM	RNA-binding domain druggable — emerging target
CD20MS4A1 AF P11836	Immun	74	82nd	NO-GO	Biologic Only	Biologics-only modality (rituximab)
BACE1BACE1 4IVT (A)	Neuro	72	81st	PURSUE	Traditional SM	Validated aspartyl protease, verubecestat reached Phase III
IRAK4IRAK4 6EGA (A)	Immun	69	76th	PURSUE	Traditional SM	Emerging kinase — emavusertib in trials
PSEN1 (gamma-secretase)PSEN1 5A63 (B)	Neuro	68	75th	PURSUE	Traditional SM	Membrane protease, semagacestat reached Phase III
TNF-alphaTNF 2AZ5 (A)	Immun	66	71st	BORDERLINE	Borderline SM	SM exist (SPD-304) but none approved
TEAD4TEAD4 5OAQ, 8CAA	Oncol	59	49th–66th	STATE-DEP	Fragment-First	YAP-bound state druggable, inhibitor-bound collapses
SOD1SOD1 AF P00441	Neuro	55	62nd	BORDERLINE	Fragment-First	Surprisingly druggable for a metalloenzyme
PCNAPCNA 1VYM, 3WGW	Oncol	53	45th–59th	STATE-DEP	Fragment-First	Ligand-bound state improves from difficult to borderline
HuntingtinHTT 6EZ8 (A)	Neuro	53	59th	BORDERLINE	Fragment-First	Large protein, borderline — not clearly druggable
TCF7L2TCF7L2 1JDH, AF	Oncol	31	0th–35th	NO-GO	Biologic Only	Transcription factor, no druggable pockets
IL-17AIL17A 5HI3 (A)	Immun	22	42nd	NO-GO	Biologic Only	Cytokine — biologics-only (secukinumab)
NRF2 (Neh2)NFE2L2 7X5F	Oncol	5	5th	NO-GO	Biologic Only	Disordered peptide — drug KEAP1 instead
BCL9BCL9 AlphaFold	Oncol	3	3rd	NO-GO	Biologic Only	Intrinsically disordered, no pockets
Tau (MAPT)MAPT AF P10636	Neuro	3	3rd	NO-GO	Biologic Only	Intrinsically disordered — clear no-go
YAP1YAP1 3KYS-B	Oncol	0	0th	NO-GO	None	Lowest possible score — no detectable pockets
alpha-SynucleinSNCA AF P37840	Neuro	0	0th	NO-GO	None	Fully disordered — lowest possible score

Cross-Indication Insights

CONSISTENT KINASE DISCRIMINATION ACROSS ALL THREE AREAS

Every kinase across all three sprints scored as PURSUE: KEAP1 (84–86), LRRK2 (91), GSK3-beta (82), JAK1 (95), BTK (88), TYK2 (82), IRAK4 (69). The engine produces consistent, high-confidence signals for this validated target class regardless of therapeutic area — a 7/7 positive control rate.

UNAMBIGUOUS IDP REJECTION ACROSS INDICATIONS

Every intrinsically disordered protein scored 0–5/100: BCL9 (3), YAP1 (0), NRF2 (5), Tau (3), alpha-synuclein (0). The engine produces clear, unambiguous no-go signals for IDPs regardless of their therapeutic area or disease relevance — preventing resource waste on structurally intractable targets.

MODALITY DISCRIMINATION — THE IMMUNOLOGY DIFFERENTIATOR

The immunology sprint uniquely tested modality discrimination. CTLA-4 (83/100) and CD20 (74/100) scored as structurally druggable but were correctly flagged as biologics-only by Layer E. This separation of structural druggability from therapeutic modality is critical for immunology targets where the biologics vs. small-molecule decision determines the entire development strategy.

28 TARGETS, ZERO FALSE POSITIVES

Across all 28 targets, no target with an approved small-molecule drug received a no-go classification, and no intrinsically disordered protein received a pursue classification. The engine's discrimination boundary is clean: validated targets score high, intractable targets score low, and the borderline cases (STAT3, HTT, TNF-alpha) are genuinely ambiguous in the field.

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