Progress Report: PHGDH ACT Domain — Lead Optimization for CNS-Penetrant AD Therapeutic (Cycle 11)
Progress Report: PHGDH ACT Domain — Lead Optimization for CNS-Penetrant AD Therapeutic (Cycle 11)
Executive Summary
No new data was added this cycle. Rankings unchanged from Cycle 10.
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 11 MCDA Deep Profile & Top-5 Selection
cycle11_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 | ||||
| BASIMGLURANT | Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1ccc(F)cc1 | 5 | 5 | 3 | tool | tool | tool | 1 | tool | Small molecule | Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1ccc(F)cc1 | CHEMBL3301626 | UPZWINBEAHDTLA-UHFFFAOYSA-N | 325.77 | 4.08 | ||||
| DIPRAGLURANT | Fc1ccc2nc(CCC#Cc3ccccn3)cn2c1 | 5 | 5 | 3 | tool | tool | tool | 1 | tool | Small molecule | Fc1ccc2nc(CCC#Cc3ccccn3)cn2c1 | CHEMBL2346738 | LZXMUJCJAWVHPZ-UHFFFAOYSA-N | 265.29 | 2.85 | ||||
| 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 | ||||
| MAVACAMTEN | CC(C)n1c(=O)cc(NC@@Hc2ccccc2)[nH]c1=O | 4 | 5 | 3 | tool | tool | tool | 1 | tool | Small molecule | CC(C)n1c(=O)cc(NC@@Hc2ccccc2)[nH]c1=O | CHEMBL4297517 | RLCLASQCAPXVLM-NSHDSACASA-N | 273.34 | 2.29 | ||||
| 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 | ||||
| RIMTUZALCAP | Cc1ccn(-c2nc(NC3CCC(F)(F)CC3)cc(N3CCOCC3… | 4 | 5 | 3 | tool | tool | tool | 1 | tool | Small molecule | Cc1ccn(-c2nc(NC3CCC(F)(F)CC3)cc(N3CCOCC3… | CHEMBL4650330 | OVLIDRAJVMUEMC-UHFFFAOYSA-N | 378.43 | 2.80 | ||||
| RASEGLURANT | Cc1cc(C)c(N)c(C#Cc2cccc(F)c2)n1 | 4 | 5 | 3 | tool | tool | tool | 1 | tool | Small molecule | Cc1cc(C)c(N)c(C#Cc2cccc(F)c2)n1 | CHEMBL3545036 | MEDCLNYIYBERKO-UHFFFAOYSA-N | 240.28 | 2.82 | ||||
| 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 | ||||
| MAVOGLURANT | COC(=O)N1CC[C@@H]2[C@H]1CCC[C@@]2(O)C#Cc… | 4 | 4 | 3 | tool | tool | tool | 1 | tool | Small molecule | COC(=O)N1CC[C@@H]2[C@H]1CCC[C@@]2(O)C#Cc… | CHEMBL3087515 | ZFPZEYHRWGMJCV-ZHALLVOQSA-N | 313.40 | 2.72 | ||||
| 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 | ||||
| occ1oc1c1ccccc1 | OCC1OC1c1ccccc1 | 4 | 5 | 3 | tool | tool | tool | 1 | tool | Small molecule | OCC1OC1c1ccccc1 | CHEMBL3661414 | PVALSANGMFRTQM-UHFFFAOYSA-N | 150.18 | 1.12 | ||||
| AFICAMTEN | CCc1nc(-c2ccc3c(c2)CC[C@H]3NC(=O)c2cnn(C… | 3 | 5 | 3 | tool | tool | tool | 1 | tool | Small molecule | CCc1nc(-c2ccc3c(c2)CC[C@H]3NC(=O)c2cnn(C… | CHEMBL4847050 | IOVAZWDIRCRMTM-OAHLLOKOSA-N | 337.38 | 2.45 | ||||
| DECOGLURANT | Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F… | 3 | 5 | 3 | tool | tool | tool | 1 | tool | Small molecule | Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F… | CHEMBL3301593 | DMJHZVARRXJSEG-UHFFFAOYSA-N | 447.34 | 4.81 | ||||
| ULACAMTEN | C[C@H]1CC[C@H](N2CC(=O)N(Cc3ccc(F)c(F)c3… | 4 | 4 | 3 | tool | tool | tool | 2 | tool | Small molecule | C[C@H]1CC[C@H](N2CC(=O)N(Cc3ccc(F)c(F)c3… | CHEMBL6 | None | None | None |
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: 0.8157, Budget Used: 1.63%, Budget Remaining: $49.1843
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=0.0264 time=197s, EXECUTOR GREEN cost=$0.0157 time=184s. MCDA Validity Summary: overall_verdict: valid_ranking, entities scored: 73, 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 | 1.63 |
| Budget Remaining Usd | 49.1843 |
| Tasks Completed | 4 |
| Risks Identified | 4 |
Agent Alert Levels
Agent Alert Levels (server-queried — not from compressed text):
PLANNER GREEN cost=$0.0017 time=17s
LEARNER GREEN cost=$0.0264 time=197s
EXECUTOR GREEN cost=$0.0157 time=184s
A.G.E. Scores
(No AGE scores this cycle)
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