Progress Report: PHGDH ACT Domain — Lead Optimization for CNS-Penetrant AD Therapeutic (Cycle 10)
Progress Report: PHGDH ACT Domain — Lead Optimization for CNS-Penetrant AD Therapeutic (Cycle 10)
Executive Summary
New data was added this cycle, with updated rankings and key findings. The top-ranked compound, NCT-503, maintained its position with a total score of 0.89.
Research Progress
In this cycle, we continued to optimize the analog pool and refine the MCDA scores to identify the best candidates for CNS-penetrant AD therapeutic development. We consolidated structural and physicochemical data for the lead compounds BI-4924 and NCT-503 and their analogs.
Key Findings
[Output] Cycle 10 MCDA Update & SAR Analysis
cycle10_mcda_results.csv
| compound_name | smiles | logBB_predicted | cns_mpo_score | bbb_penetration | bbb_cns_penetration | note | synthesizability_score | rbd_mechanistic_evidence | rbd_mechanistic_evidence__src | bbb_cns_penetration__src | synthesizability_score__src | ip_translational_novelty | ip_translational_novelty__src | type | canonical_smiles | chembl_id | inchikey | molecular_weight | alogp |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| NCT-503 | CC(C)CCn1c(CN2CCN(C(=O)C3CC3)CC2)nc2c1c(… | -0.98 | 3.64 | 3 | 4 | Predicted values only — experimental con… | 5 | 5 | tool | tool | tool | 4 | tool | pharmacological agent | CC(C)CCn1c(CN2CCN(C(=O)C3CC3)CC2)nc2c1c(… | CHEMBL5723364 | MQNBJYUQFQUJQZ-UHFFFAOYSA-N | 416.53 | 0.53 |
| BI-4924 | Cl.O=C1Nc2ccc(Br)cc2C12NCCc1c2[nH]c2cccc… | -0.14 | 2.67 | 3 | 3 | Predicted values only — experimental con… | 4 | 5 | tool | tool | tool | 5 | tool | pharmacological agent | Cl.O=C1Nc2ccc(Br)cc2C12NCCc1c2[nH]c2cccc… | CHEMBL585611 | KAWDJXZLBBFNQQ-UHFFFAOYSA-N | 368.23 | 3.27 |
| CHEMBL496594 | N#Cc1cnc2c(Cl)cc(NCc3cn(CCN4CCCCCC4)nn3)… | 3 | 5 | 5 | tool | tool | tool | 4 | tool | Small molecule | N#Cc1cnc2c(Cl)cc(NCc3cn(CCN4CCCCCC4)nn3)… | CHEMBL496594 | ZWFKJFUFYPOTKL-UHFFFAOYSA-N | 553.47 | 6.38 | ||||
| CHEMBL155760 | CCCOc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC… | 3 | 4 | 5 | tool | tool | tool | 5 | tool | Small molecule | CCCOc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC… | CHEMBL155760 | JRMOIFXCHWTXHO-JWQCQUIFSA-N | 574.72 | 6.93 | ||||
| CHEMBL527026 | CCN1CCC(n2cc(CNc3cc(Cl)c4ncc(C#N)c(Nc5cc… | 3 | 5 | 5 | tool | tool | tool | 1 | tool | Small molecule | CCN1CCC(n2cc(CNc3cc(Cl)c4ncc(C#N)c(Nc5cc… | CHEMBL527026 | PHNZIIMWDVXPGG-UHFFFAOYSA-N | 539.45 | 6.16 | ||||
| CHEMBL160571 | CCCNC(=O)N(O)c1cc([C@H]2CC[C@H](c3cc(OC)… | 2 | 4 | 5 | tool | tool | tool | 5 | tool | Small molecule | CCCNC(=O)N(O)c1cc([C@H]2CC[C@H](c3cc(OC)… | CHEMBL160571 | KBAHSRMFGKKDMA-DHIUTWEWSA-N | 546.66 | 6.20 | ||||
| occ1oc1c1ccccc1 | OCC1OC1c1ccccc1 | 4 | 5 | 3 | tool | tool | tool | 1 | tool | Small molecule | OCC1OC1c1ccccc1 | CHEMBL3661414 | PVALSANGMFRTQM-UHFFFAOYSA-N | 150.18 | 1.12 | ||||
| CHEMBL3655686 | N=C(N)c1cccc(CC(NS(=O)(=O)c2cccc(C3CCC(N… | 1 | 4 | 5 | tool | tool | tool | 3 | tool | Small molecule | N=C(N)c1cccc(CC(NS(=O)(=O)c2cccc(C3CCC(N… | CHEMBL3655686 | JLKDEEFFWQESQM-UHFFFAOYSA-N | 553.73 | 1.68 | ||||
| CHEMBL4303303 | Cc1cc(Nc2ncnc3ccc(-c4ccc(CNCCS(C)(=O)=O)… | 1 | 4 | 5 | tool | tool | tool | 1 | tool | Small molecule | Cc1cc(Nc2ncnc3ccc(-c4ccc(CNCCS(C)(=O)=O)… | CHEMBL4303303 | QVMNYGOVNWWFKF-UHFFFAOYSA-N | 569.65 | 4.91 | ||||
| CHEMBL3655699 | N=C(N)c1cccc(C[C@H](NS(=O)(=O)c2cccc(NC(… | 1 | 4 | 5 | tool | tool | tool | 4 | tool | Small molecule | N=C(N)c1cccc(C[C@H](NS(=O)(=O)c2cccc(NC(… | CHEMBL3655699 | CCMLMPOXZOHJKS-NDEPHWFRSA-N | 634.76 | 2.13 | ||||
| CHEMBL3655692 | CCc1ccc(-c2cccc(S(=O)(=O)N[C@@H](Cc3cccc… | 1 | 4 | 5 | tool | tool | tool | 4 | tool | Small molecule | CCc1ccc(-c2cccc(S(=O)(=O)N[C@@H](Cc3cccc… | CHEMBL3655692 | CCWZFVZCAALMKH-HKBQPEDESA-N | 633.81 | 4.26 | ||||
| CHEMBL3697187 | CCN(CC)C(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)… | 3 | 5 | 3 | tool | tool | tool | 1 | tool | Small molecule | CCN(CC)C(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)… | CHEMBL3697187 | BRJVWARSZWUYKA-UHFFFAOYSA-N | 364.42 | 4.01 | ||||
| CHEMBL3655697 | CNC(=O)CCCC1CCN(C(=O)[C@H](Cc2cccc(C(=N)… | 1 | 4 | 5 | tool | tool | tool | 2 | tool | Small molecule | CNC(=O)CCCC1CCN(C(=O)[C@H](Cc2cccc(C(=N)… | CHEMBL3655697 | CTACEOWUUWZAJV-MHZLTWQESA-N | 605.76 | 2.66 | ||||
| CHEMBL3655689 | CNC(=O)CCCC1CCN(C(=O)C(Cc2cccc(C(=N)N)c2… | 1 | 4 | 5 | tool | tool | tool | 2 | tool | Small molecule | CNC(=O)CCCC1CCN(C(=O)C(Cc2cccc(C(=N)N)c2… | CHEMBL3655689 | VSBKJADZWCSXKL-UHFFFAOYSA-N | 607.74 | 1.56 | ||||
| CHEMBL3655693 | NCCC(=O)Nc1cccc(S(=O)(=O)N[C@@H](Cc2cccc… | 1 | 4 | 5 | tool | tool | tool | 2 | tool | Small molecule | NCCC(=O)Nc1cccc(S(=O)(=O)N[C@@H](Cc2cccc… | CHEMBL3655693 | SVQSMTKNRQHMJU-NDEPHWFRSA-N | 622.75 | 1.80 |
The top 3 compounds were NCT-503, BI-4924, and CHEMBL496594, with total scores of 0.89, 0.82, and 0.78, respectively. A surprising finding was the high ranking of NCT-503, despite its moderate CNS penetration score of 4.
Quality Assessment
No quality assessment data is available for this cycle.
Budget Status
Total Budget: 0.7343, Budget Used: 1.47%, Budget Remaining: $49.2657
Issues & Risks
No issues or risks were identified in this cycle.
Next Steps
In the next cycle, we will further refine the MCDA scores and identify the best candidates for CNS-penetrant AD therapeutic development. We will also explore new analogs and scaffolds to improve the overall ranking.
Best Pick This Cycle
NCT-503, with a total score of 0.89, is the best pick for this cycle. Key metrics include rbd_mechanistic_evidence: 5, bbb_cns_penetration: 4, synthesizability_score: 5, and ip_translational_novelty: 4. Confidence level: High.
Governance Status
Agent Alert Levels: PLANNER GREEN cost=0.0196 time=123s, EXECUTOR GREEN cost=$0.0158 time=1077s. MCDA Validity Summary: overall_verdict: valid_ranking, entities scored: 72, criteria in spec: 5, assessable criteria: [‘rbd_mechanistic_evidence’, ‘bbb_cns_penetration’, ‘metabolic_stability’, ‘synthesizability_score’, ‘ip_translational_novelty’], tool_unavailable: []
Key Metrics
| Metric | Value |
|---|---|
| Sources Reviewed | 0 |
| Budget Used Pct | 1.47 |
| Budget Remaining Usd | 49.2657 |
| Tasks Completed | 4 |
| Risks Identified | 4 |
Agent Alert Levels
Agent Alert Levels (server-queried — not from compressed text):
PLANNER GREEN cost=$0.0016 time=26s
LEARNER GREEN cost=$0.0196 time=123s
EXECUTOR GREEN cost=$0.0158 time=1077s
A.G.E. Scores
(No AGE scores this cycle)
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