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Lonitoclax
Lonitoclax
CAS 2952589-57-8
MF C43H45ClN4O5 MW733.3 g/mol
5-[5-chloro-2-[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-N-(4-hydroxyphenyl)-N-[(3-methoxy-2-methylphenyl)methyl]-1,2-dimethylpyrrole-3-carboxamide
- 1H-Pyrrole-3-carboxamide, 5-[5-chloro-2-[[(3S)-3,4-dihydro-3-(4-morpholinylmethyl)-2(1H)-isoquinolinyl]carbonyl]phenyl]-N-(4-hydroxyphenyl)-N-[(3-methoxy-2-methylphenyl)methyl]-1,2-dimethyl-
- 5-(5-Chloro-2-(((3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2-(1-H)-yl)carbonyl)phenyl)-N-4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide
- 5-[5-chloro-2-[(3S)-3-(morpholinomethyl)- 3,4-dihydro-1H-isoquinoline-2- carbonyl]phenyl]-N-(4-hydroxyphenyl)-N- [(3-methoxy-2-methyl-phenyl)methyl]-1,2- dimethyl-pyrrole-3-carboxamide
- 5-{5-Chloro-2-[(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl]phenyl}-N-(4-hydroxyphenyl)-N-[(3-methoxy-2-methylphenyl)methyl]-1,2-dimethyl-1H-pyrrole-3-carboxamide
5-(5-chloro-2-{(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl}phenyl)-N-(4-
hydroxyphenyl)-N-[(3-methoxy-2-methylphenyl)methyl]-1,2-dimethyl-1H-pyrrole-3-carboxamide
B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, ZE50-0134, ZE50 0134, Lomond Therapeutics, CANCER, 76NBC3X6A3
Lonitoclax (also known as ZE50-0134) is an investigational, next-generation, orally administered B-cell lymphoma 2 (Bcl-2) inhibitor being developed for the treatment of hematologic malignancies like Acute Myeloid Leukemia (AML) and Chronic Lymphocytic Leukemia (CLL). Developed by Lomond Therapeutics, the drug is engineered as a highly selective option to improve upon existing first-generation Bcl-2 inhibitors like venetoclax.
Mechanism and Advantages Over Venetoclax
Unlike earlier therapies, lonitoclax features a unique binding mode and a structurally distinct chemotype. Its design yields several pharmacology advantages:
- Higher Selectivity: It binds tightly to Bcl-2 while demonstrating exceptional selectivity over Bcl-xL, which helps lower hematologic toxicities.
- Limited Immune Suppression: In preclinical data, lonitoclax spared healthy non-malignant immune cells (B cells, CD8 T cells, and NK cells), a major shift from the immunosuppressive profile of venetoclax.
- Reduced Drug Interaction & Accumulation: It features a shorter half-life (~9–10 hours) and minimal CYP3A4 (P4503A4) inhibition. This prevents the drug from building up dangerously and mitigates the risk of Tumor Lysis Syndrome (TLS), potentially enabling safer outpatient treatments.
Clinical Development Status
Lonitoclax is currently advancing through early-phase clinical trials:
- IND Clearances: The U.S. FDA cleared Investigational New Drug (IND) applications evaluating lonitoclax for CLL/SLL and as a combination treatment for relapsed or refractory AML.
- Healthy Volunteer Studies: Phase 1 single ascending dose (SAD) studies in healthy adults confirmed that the drug is well tolerated with linear pharmacokinetics and no significant safety issues. Target engagement was confirmed through plasma apoptosis assays.
- Combination Trials: Active Phase 1b multicenter trials are underway evaluating the safety, efficacy, and synergy of lonitoclax when combined with hypomethylating agents like azacitidine in AML patients.
SYN
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023129553&_cid=P11-MQVQMH-93381-1
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References
- Bcl-2 inhibitorsPublication Number: WO-2023129553-A1Priority Date: 2021-12-29
- BCL-2 InhibitorsPublication Number: US-2025115577-A1Priority Date: 2021-12-29
- Bcl-2 inhibitorsPublication Number: EP-4457223-A1Priority Date: 2021-12-29
///////Lonitoclax, ANAX LABS, B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, ZE50-0134, ZE50 0134, Lomond Therapeutics, CANCER, 76NBC3X6A3
Asaretoclax
Asaretoclax
CAS 2363074-01-3
MF C47H57F2N7O7S, MW 902.1 g/mol
4-[4-[[2-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[(4-hydroxy-4-methylcyclohexyl)methylamino]-3-nitrophenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide
B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, GY6FD5FXA3, HY 159817, ABT 263
Asaretoclax is an orally bioavailable inhibitor of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), with potential pro-apoptotic and antineoplastic activities. Upon oral administration, asaretoclax targets, binds to and inhibits the activity of Bcl-2. This restores apoptotic processes in tumor cells. Bcl-2 is overexpressed in many cancers and plays an important role in the negative regulation of apoptosis; its expression is associated with increased drug resistance and tumor cell survival.
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US309776623&_cid=P21-MJZ42N-73938-1
Example 34
2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1l-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide
Intermediate 18
Intermediate 18
4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide
Intermediate 18 was prepared following a procedure described in WO2014/165044A1. LC/MS (ESI) m/z 344.1 [M+H] +.
Intermediate 30
Intermediate 30
2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic Acid
| Step 1: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (Intermediate 30-1) was prepared following the procedure described in Step 1, Route C for Intermediate 28 using Intermediate 24 in place of Intermediate 22. LCMS (ESI) m/z 591.2 [M+H] +. |
Example 34 was prepared following General Procedure A using Intermediate 30 and Intermediate 18. 1H NMR (400 MHz, DMSO-d 6) δ 11.70 (s, 1H), 11.40 (br s, 1H), 8.59-8.49 (m, 2H), 8.04 (d, J=2.0 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.53-7.48 (m, 3H), 7.06 (d, J=9.2 Hz, 1H), 6.72 (d, J=7.2 Hz, 1H), 6.38 (s, 1H), 6.25 (s, 1H), 5.99 (t, J=56.8 Hz, 1H), 4.25 (s, 1H), 3.33-3.25 (m, 2H), 3.18-3.05 (m, 4H), 2.97 (s, 2H), 2.40-2.28 (m, 4H), 2.05-1.95 (m, 2H), 1.94 (s, 6H), 1.71-1.59 (m, 5H), 1.58-1.49 (m, 2H), 1.39-1.28 (m, 2H), 1.27-1.20 (m, 2H), 1.18-1.09 (m, 2H), 1.10 (s, 3H), 0.83 (s, 6H); LC/MS (ESI) m/z 902.6 [M+H] +.
SYN
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US384526484&_cid=P21-MJZ3XL-69589-1
PAT
Publication Number: US-2021009543-A1
Priority Date: 2018-01-10
- Benzamide compoundsPublication Number: CN-118084904-APriority Date: 2018-01-10
- Benzamide compoundsPublication Number: EP-4556469-A1Priority Date: 2018-01-10
- Benzamide compounds as bci inhibitors for the treatment of hivPublication Number: EP-3740487-B1Priority Date: 2018-01-10Grant Date: 2025-01-08
- Benzamide compoundsPublication Number: US-11344546-B2Priority Date: 2018-01-10Grant Date: 2022-05-31
- Benzamide compoundsPublication Number: US-11318134-B2Priority Date: 2018-01-10Grant Date: 2022-05-03
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/////////Asaretoclax, B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, GY6FD5FXA3, HY 159817, ABT 263
Zamzetoclax
Zamzetoclax
CAS 2388470-64-0
MF C38H46ClN5O6S MW736.32
N-[(3′R,4S,6′R,7′S,8′E,11′S)-7-chloro-7′-methoxy-11′-methyl-13′,15′-dioxospiro[2,3-dihydro-1H-naphthalene-4,22′-20-oxa-13λ6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-13′-yl]-3-methoxy-1-methylpyrazole-4-carboxamide
- 1H-Pyrazole-4-carboxamide, N-[(1’S,10S,12S,14E,16S,16aR,18aR)-6′-chloro-3′,4′,8,11,12,13,16,16a,17,18,18a,19-dodecahydro-16-methoxy-12-methyl-10-oxido-8-oxospiro[5,7-etheno-1H-10lambda4-cyclobut[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecine-2(3H),1′(2’H)-naphthalen]-10-yl]-3-methoxy-1-methyl-
- N-[(1’S,10S,12S,14E,16S,16aR,18aR)-6′-Chloro-3′,4′,8,11,12,13,16,16a,17,18,18a,19-dodecahydro-16-methoxy-12-methyl-10-oxido-8-oxospiro[5,7-etheno-1H-10lambda4-cyclobut[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecine-2(3H),1′(2’H)-naphthalen]-10-yl]-3-methoxy-1-methyl-1H-pyrazole-4-carboxamide
B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, RRS8GZU2UN
Zamzetoclax (compound 1) is a potential Mcl-1 inhibitor.
Publication Name: Journal of Medicinal Chemistry
Publication Date: 2023-04-28
PMID: 37114951
DOI: 10.1021/acs.jmedchem.2c01953
SYN
WO 2019/222112
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019222112&_cid=P12-MJ7Z15-98773-1
Example 154
[0447] Example 154 was synthesized in the same manner as Example 18 using 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109. Example 109 (620 mg, 1.04 mmol) was dissolved in dichloromethane (12 mL). 3-Methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (324 mg, 2.08 mmol, 2 equiv.) and N-(3-dimethylaminopropyl)-N¢-ethylcarbodiimide hydrochloride (400 mg, 2.08 mmol, 2 equiv.) were added. The reaction mixture was stirred for 5 minutes at room temperature before DMAP (253 mg, 2.08 mmol, 2 equiv.) was added in a single portion. The reaction mixture was stirred overnight at room temperature and the progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by Gilson reverse phase prep HPLC (60-100% ACN/H2O with 0.1% TFA) to give Example 154.1H NMR (400 MHz, methanol-d4) d 8.07 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.22– 7.10 (m, 3H), 6.92 (d, J = 8.2 Hz, 1H), 6.20– 6.05 (m, 1H), 5.63 (dd, J = 15.5, 8.0 Hz, 1H), 4.10 (d, J = 12.0 Hz, 1H), 4.06 (s, 4H), 3.91– 3.83 (m, 1H), 3.82 (s, 3H), 3.79 (s, 1H), 3.72 (d, J = 14.4 Hz, 1H), 3.38 (d, J = 14.5 Hz, 1H), 3.30 (s, 3H), 3.09 (dd, J = 15.1, 10.0 Hz, 1H), 2.89– 2.72 (m, 2H), 2.51 (d, J = 26.7 Hz, 2H), 2.24 (dd, J = 10.9, 6.0 Hz, 2H), 2.12 (d, J = 13.7 Hz, 1H), 2.02– 1.70 (m, 4H), 1.54– 1.40 (m, 1H), 1.14 (d, J = 6.1 Hz, 3H). LCMS-ESI+ (m/z): calcd for C38H46ClN5O6S: 735.28; found: 735.94.
SYN
WO 2019/222112 discloses novel 3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene] derivatives that are active against MCL-1. For example, Compound 1 (below) has been shown to be an effective MCL-1 inhibitor
SYN
SYN
PAT
- Mcl-1 inhibitorsPublication Number: US-2019352271-A1Priority Date: 2018-05-14
- Mcl-1 inhibitorsPublication Number: US-2020331870-A1Priority Date: 2018-05-14
- MCL-1 inhibitorsPublication Number: US-10988451-B2Priority Date: 2018-05-14Grant Date: 2021-04-27
- MCL-1 inhibitorsPublication Number: US-11643400-B2Priority Date: 2018-05-14Grant Date: 2023-05-09
- Mcl-1 inhibitorsPublication Number: US-2023312490-A1Priority Date: 2018-05-14
- Processes and intermediates for preparing mcl1 inhibitorsPublication Number: US-2023013713-A1Priority Date: 2019-11-26
- Processes and intermediates for preparing MCL1 inhibitorsPublication Number: US-11760736-B2Priority Date: 2019-11-26Grant Date: 2023-09-19
- Mcl1 inhibitorsPublication Number: US-2021171543-A1Priority Date: 2019-11-12
- Mcl1 inhibitorsPublication Number: US-2023348494-A1Priority Date: 2019-11-12
- MCL-1 inhibitorsPublication Number: US-10703733-B2Priority Date: 2018-05-14Grant Date: 2020-07-07
- Salts and polymorphs of certain mcl-1 inhibitorsPublication Number: US-2023357274-A1Priority Date: 2022-05-04
- Combination mcl-1 inhibitors with anti-body drug conjugatesPublication Number: US-2022409736-A1Priority Date: 2021-06-11
- Processes and intermediates for preparing mcl1 inhibitorsPublication Number: US-2022177409-A1Priority Date: 2020-11-19
- Processes and intermediates for preparing mcl1 inhibitorsPublication Number: US-2021179570-A1Priority Date: 2019-11-26
- Processes and intermediates for preparing MCL1 inhibitorsPublication Number: US-11325891-B2Priority Date: 2019-11-26Grant Date: 2022-05-10
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///////////zamzetoclax, B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, RRS8GZU2UN
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