2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)acetamide

ID: ALA4464889

PubChem CID: 155530809

Max Phase: Preclinical

Molecular Formula: C43H49N11O7

Molecular Weight: 831.93

Molecule Type: Unknown

Names and Identifiers

Canonical SMILES:  CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(CC(=O)NCCCCNc5cccc6c5C(=O)N(C5CCC(=O)NC5=O)C6=O)CC4)cn3)nc2n(C2CCCC2)c1=O

Standard InChI:  InChI=1S/C43H49N11O7/c1-25-30-23-47-43(50-38(30)53(27-8-3-4-9-27)41(60)36(25)26(2)55)48-33-14-12-28(22-46-33)52-20-18-51(19-21-52)24-35(57)45-17-6-5-16-44-31-11-7-10-29-37(31)42(61)54(40(29)59)32-13-15-34(56)49-39(32)58/h7,10-12,14,22-23,27,32,44H,3-6,8-9,13,15-21,24H2,1-2H3,(H,45,57)(H,49,56,58)(H,46,47,48,50)

Standard InChI Key:  ZDYIWDFMTLECCN-UHFFFAOYSA-N

Molfile:  

 
     RDKit          2D

 61 68  0  0  0  0  0  0  0  0999 V2000
    4.2083  -13.2744    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    4.9248  -12.8610    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.9220  -12.0304    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    4.2065  -11.6212    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.4935  -12.8614    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.4976  -12.0386    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.7909  -11.6259    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.0756  -12.0314    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.0715  -12.8544    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.7827  -13.2716    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    2.7961  -10.8008    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.3637  -11.6144    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.3690  -10.7893    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    0.6466  -12.0223    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.3545  -13.2626    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    2.7827  -14.1001    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.1135  -14.5826    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.3656  -15.3682    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.1907  -15.3712    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.4484  -14.5875    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.6399  -13.2723    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    6.3538  -12.8587    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.0656  -13.2706    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.7790  -12.8576    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.7782  -12.0317    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.0579  -11.6205    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.3476  -12.0358    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    8.4859  -11.6183    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    9.2015  -12.0309    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.9126  -11.6198    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.9146  -10.7944    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    9.1989  -10.3818    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.4816  -10.7945    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.6294  -10.3825    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.3436  -10.7957    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.0585  -10.3838    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   11.3429  -11.6207    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   12.7726  -10.7970    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.4875  -10.3850    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.2016  -10.7982    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.9165  -10.3864    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.6306  -10.7995    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   16.3455  -10.3876    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.7723   -9.5636    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.0532   -9.1506    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.3417   -9.5642    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.7712  -10.3896    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.0561  -10.7960    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.2216  -11.6017    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.0391  -11.6933    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   18.3786  -10.9441    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.6653  -12.2110    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   19.1868  -10.7781    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   18.4438  -12.4070    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.0243  -13.1186    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.4285  -13.8337    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.2538  -13.8435    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.6733  -13.1320    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   19.2676  -12.4106    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.6856  -11.6994    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   19.6588  -14.5623    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
  5  1  1  0
  1  2  2  0
  2  3  1  0
  3  4  2  0
  4  6  1  0
  5  6  2  0
  5 10  1  0
  6  7  1  0
  7  8  2  0
  8  9  1  0
  9 10  1  0
  7 11  1  0
  8 12  1  0
 12 13  2  0
 12 14  1  0
  9 15  2  0
 16 17  1  0
 17 18  1  0
 18 19  1  0
 19 20  1  0
 20 16  1  0
 10 16  1  0
  2 21  1  0
 21 22  1  0
 22 23  2  0
 23 24  1  0
 24 25  2  0
 25 26  1  0
 26 27  2  0
 27 22  1  0
 28 29  1  0
 28 33  1  0
 29 30  1  0
 30 31  1  0
 31 32  1  0
 32 33  1  0
 25 28  1  0
 31 34  1  0
 34 35  1  0
 35 36  1  0
 35 37  2  0
 36 38  1  0
 38 39  1  0
 39 40  1  0
 40 41  1  0
 41 42  1  0
 42 43  1  0
 43 48  2  0
 47 44  2  0
 44 45  1  0
 45 46  2  0
 46 43  1  0
 47 48  1  0
 48 49  1  0
 49 50  1  0
 50 51  1  0
 51 47  1  0
 49 52  2  0
 51 53  2  0
 54 55  1  0
 54 59  1  0
 55 56  1  0
 56 57  1  0
 57 58  1  0
 58 59  1  0
 50 54  1  0
 59 60  2  0
 57 61  2  0
M  END

Alternative Forms

1. Parent:

   

   ALA4464889

   ---

Molecule Features

Natural Product: No

Oral: No

Chemical Probe: No

Parenteral: No

Molecule Type: Unknown

Topical: No

First In Class: No

Black Box: No

Chirality: No

Availability: No

Prodrug: No

Calculated Properties

Molecular Weight: 831.93

Molecular Weight (Monoisotopic): 831.3816

AlogP: 3.09

#Rotatable Bonds: 14

Polar Surface Area: 220.93

Molecular Species: NEUTRAL

HBA: 15

HBD: 4

#RO5 Violations: 2

HBA (Lipinski): 18

HBD (Lipinski): 4

#RO5 Violations (Lipinski): 2

CX Acidic pKa: 11.15

CX Basic pKa: 6.22

CX LogP: 2.59

CX LogD: 2.57

Aromatic Rings: 4

Heavy Atoms: 61

QED Weighted: 0.08

Np Likeness Score: -1.10

References

1. Rana S, Bendjennat M, Kour S, King HM, Kizhake S, Zahid M, Natarajan A..  (2019)  Selective degradation of CDK6 by a palbociclib based PROTAC.,  29  (11): [PMID:30935795] [10.1016/j.bmcl.2019.03.035]

2. Gray, N S NS and 12 more authors.  1998-07-24  Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors.  [PMID:9677190]

3. Kubo, A A and 9 more authors.  1999-12  The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin-dependent kinase 4.  [PMID:10632371]

4. Soni, R R and 7 more authors.  2000-09-07  Inhibition of cyclin-dependent kinase 4 (Cdk4) by fascaplysin, a marine natural product.  [PMID:10973815]

5. Lane, M E ME and 9 more authors.  2001-08-15  A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells.  [PMID:11507069]

6. Tavares, Francis X FX and 7 more authors.  2004-09-09  N-Phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular efficacy.  [PMID:15341487]

7. Fry, David W DW and 10 more authors.  2004-11  Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts.  [PMID:15542782]

8. Pennati, Marzia M and 12 more authors.  2005-09  Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation.  [PMID:16170024]

9. Sridhar, Jayalakshmi J, Akula, Nagaraju N and Pattabiraman, Nagarajan N.  2006-03-24  Selectivity and potency of cyclin-dependent kinase inhibitors.  [PMID:16584130]

10. DePinto, Wanda W and 19 more authors.  2006-11  In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials.  [PMID:17121911]

11. Joshi, Kalpana S KS and 7 more authors.  2007-03  In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00.  [PMID:17363486]

12. Squires, Matthew S MS and 7 more authors.  2009-02  Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines.  [PMID:19174555]

13. Cirstea, D D and 15 more authors.  2013-12  Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs.  [PMID:23807770]

14. Gelbert, Lawrence M LM and 16 more authors.  2014-10  Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine.  [PMID:24919854]

15. Paiva, Cody C and 8 more authors.  2015  Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells.  [PMID:26606677]

16. Bisi, John E JE, Sorrentino, Jessica A JA, Roberts, Patrick J PJ, Tavares, Francis X FX and Strum, Jay C JC.  2016-05  Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression.  [PMID:26826116]

17. Klaeger, Susan S and 47 more authors.  2017-12-01  The target landscape of clinical kinase drugs.  [PMID:29191878]

18. Wang, Yan Y and 10 more authors.  2018-03-01  Design and synthesis of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine as a highly potent and selective cyclin-dependent kinases 4 and 6 inhibitors and the discovery of structure-activity relationships.  [PMID:29429832]

19. Tear, Westley F and 16 more authors.  2020-01-23  Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-b]pyridazines for the Treatment of Human African Trypanosomiasis.  [PMID:31846577]

20. Wu, Tizhi and 6 more authors.  2020-11-25  Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.  [PMID:32866383]

Source

Source(1):

• Scientific Literature