Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTK0FEA)

• DTT Name: Leucine-rich repeat kinase 2 (LRRK2)
• Synonyms: PARK8; Leucine-rich repeat serine/threonine-protein kinase 2; Dardarin
• Gene Name: LRRK2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: LRRK2_HUMAN
• TTD ID: T08123
• EC Number: EC 2.7.11.1
• Sequence:
  MASGSCQGCEEDEETLKKLIVRLNNVQEGKQIETLVQILEDLLVFTYSERASKLFQGKNI
  HVPLLIVLDSYMRVASVQQVGWSLLCKLIEVCPGTMQSLMGPQDVGNDWEVLGVHQLILK
  MLTVHNASVNLSVIGLKTLDLLLTSGKITLLILDEESDIFMLIFDAMHSFPANDEVQKLG
  CKALHVLFERVSEEQLTEFVENKDYMILLSALTNFKDEEEIVLHVLHCLHSLAIPCNNVE
  VLMSGNVRCYNIVVEAMKAFPMSERIQEVSCCLLHRLTLGNFFNILVLNEVHEFVVKAVQ
  QYPENAALQISALSCLALLTETIFLNQDLEEKNENQENDDEGEEDKLFWLEACYKALTWH
  RKNKHVQEAACWALNNLLMYQNSLHEKIGDEDGHFPAHREVMLSMLMHSSSKEVFQASAN
  ALSTLLEQNVNFRKILLSKGIHLNVLELMQKHIHSPEVAESGCKMLNHLFEGSNTSLDIM
  AAVVPKILTVMKRHETSLPVQLEALRAILHFIVPGMPEESREDTEFHHKLNMVKKQCFKN
  DIHKLVLAALNRFIGNPGIQKCGLKVISSIVHFPDALEMLSLEGAMDSVLHTLQMYPDDQ
  EIQCLGLSLIGYLITKKNVFIGTGHLLAKILVSSLYRFKDVAEIQTKGFQTILAILKLSA
  SFSKLLVHHSFDLVIFHQMSSNIMEQKDQQFLNLCCKCFAKVAMDDYLKNVMLERACDQN
  NSIMVECLLLLGADANQAKEGSSLICQVCEKESSPKLVELLLNSGSREQDVRKALTISIG
  KGDSQIISLLLRRLALDVANNSICLGGFCIGKVEPSWLGPLFPDKTSNLRKQTNIASTLA
  RMVIRYQMKSAVEEGTASGSDGNFSEDVLSKFDEWTFIPDSSMDSVFAQSDDLDSEGSEG
  SFLVKKKSNSISVGEFYRDAVLQRCSPNLQRHSNSLGPIFDHEDLLKRKRKILSSDDSLR
  SSKLQSHMRHSDSISSLASEREYITSLDLSANELRDIDALSQKCCISVHLEHLEKLELHQ
  NALTSFPQQLCETLKSLTHLDLHSNKFTSFPSYLLKMSCIANLDVSRNDIGPSVVLDPTV
  KCPTLKQFNLSYNQLSFVPENLTDVVEKLEQLILEGNKISGICSPLRLKELKILNLSKNH
  ISSLSENFLEACPKVESFSARMNFLAAMPFLPPSMTILKLSQNKFSCIPEAILNLPHLRS
  LDMSSNDIQYLPGPAHWKSLNLRELLFSHNQISILDLSEKAYLWSRVEKLHLSHNKLKEI
  PPEIGCLENLTSLDVSYNLELRSFPNEMGKLSKIWDLPLDELHLNFDFKHIGCKAKDIIR
  FLQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQLMKTKKSDLGMQSATVGIDVKDWPIQI
  RDKRKRDLVLNVWDFAGREEFYSTHPHFMTQRALYLAVYDLSKGQAEVDAMKPWLFNIKA
  RASSSPVILVGTHLDVSDEKQRKACMSKITKELLNKRGFPAIRDYHFVNATEESDALAKL
  RKTIINESLNFKIRDQLVVGQLIPDCYVELEKIILSERKNVPIEFPVIDRKRLLQLVREN
  QLQLDENELPHAVHFLNESGVLLHFQDPALQLSDLYFVEPKWLCKIMAQILTVKVEGCPK
  HPKGIISRRDVEKFLSKKRKFPKNYMSQYFKLLEKFQIALPIGEEYLLVPSSLSDHRPVI
  ELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLEISPYMLSGRERALRPNRMYWRQGIYL
  NWSPEAYCLVGSEVLDNHPESFLKITVPSCRKGCILLGQVVDHIDSLMEEWFPGLLEIDI
  CGEGETLLKKWALYSFNDGEEHQKILLDDLMKKAEEGDLLVNPDQPRLTIPISQIAPDLI
  LADLPRNIMLNNDELEFEQAPEFLLGDGSFGSVYRAAYEGEEVAVKIFNKHTSLRLLRQE
  LVVLCHLHHPSLISLLAAGIRPRMLVMELASKGSLDRLLQQDKASLTRTLQHRIALHVAD
  GLRYLHSAMIIYRDLKPHNVLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEGTPGFRA
  PEVARGNVIYNQQADVYSFGLLLYDILTTGGRIVEGLKFPNEFDELEIQGKLPDPVKEYG
  CAPWPMVEKLIKQCLKENPQERPTSAQVFDILNSAELVCLTRRILLPKNVIVECMVATHH
  NSRNASIWLGCGHTDRGQLSFLDLNTEGYTSEEVADSRILCLALVHLPVEKESWIVSGTQ
  SGTLLVINTEDGKKRHTLEKMTDSVTCLYCNSFSKQSKQKNFLLVGTADGKLAIFEDKTV
  KLKGAAPLKILNIGNVSTPLMCLSESTNSTERNVMWGGCGTKIFSFSNDFTIQKLIETRT
  SQLFSYAAFSDSNIITVVVDTALYIAKQNSPVVEVWDKKTEKLCGLIDCVHFLREVMVKE
  NKESKHKMSYSGRVKTLCLQKNTALWIGTGGGHILLLDLSTRRLIRVIYNFCNSVRVMMT
  AQLGSLKNVMLVLGYNRKNTEGTQKQKEIQSCLTVWDINLPHEVQNLEKHIEVRKELAEK
  MRRTSVE
• Function: Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes. Together with RAB29, plays a role in the retrograde trafficking pathway for recycling proteins, such as mannose 6 phosphate receptor (M6PR), between lysosomes and the Golgi apparatus in a retromer-dependent manner. Regulates neuronal process morphology in the intact central nervous system (CNS). Plays a role in synaptic vesicle trafficking. Phosphorylates PRDX3. Has GTPase activity. May play a role in the phosphorylation of proteins central to Parkinson disease. Plays an important role in recuiting SEC16A to endoplasmic reticulum exit sites (ERES) and in regulating ER to Golgi vesicle-mediated transport and ERES organization.
• KEGG Pathway:
  Parkinson disease (hsa05012)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway: PTK6 promotes HIF1A stabilization (R-HSA-8857538)

Molecular Interaction Atlas (MIA) of This DTT

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BIIB094	DMLUO5K	Parkinson disease	8A00.0	Phase 1	[2]
DNL151	DMZT89C	Parkinson disease	8A00.0	Phase 1	[1]
DNL201	DMFEORD	Parkinson disease	8A00.0	Phase 1	[1]

32 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aminopyridine derivative 2	DMUGZNL	N. A.	N. A.	Patented	[3]
Aminopyridine derivative 3	DMSLJE8	N. A.	N. A.	Patented	[3]
Azaindazole derivative 1	DM3S0LI	N. A.	N. A.	Patented	[3]
Azaindazole derivative 2	DMEYS3V	N. A.	N. A.	Patented	[3]
Azaindazole derivative 3	DMOV9XA	N. A.	N. A.	Patented	[3]
Azaindazole derivative 4	DMX3MNT	N. A.	N. A.	Patented	[3]
Bidentate ligands of Markush derivative 1	DMB08D3	N. A.	N. A.	Patented	[3]
Bidentate ligands of Markush derivative 2	DM2QNMC	N. A.	N. A.	Patented	[3]
Fused thiophene derivative 1	DMV7IX4	N. A.	N. A.	Patented	[3]
Hydrazide derivative 3	DM3U79M	N. A.	N. A.	Patented	[3]
Hydrazide derivative 4	DM1HI8Q	N. A.	N. A.	Patented	[3]
Hydrazide derivative 5	DM6RLVB	N. A.	N. A.	Patented	[3]
Oxindole derivative 2	DM6ZYMC	N. A.	N. A.	Patented	[3]
Oxindole derivative 3	DM0ENF3	N. A.	N. A.	Patented	[3]
Oxindole derivative 4	DM3U58I	N. A.	N. A.	Patented	[3]
PMID28117607-Compound-20	DMAXS57	N. A.	N. A.	Patented	[3]
PMID28117607-Compound-21	DMS8OTG	N. A.	N. A.	Patented	[3]
PMID28117607-Compound-4	DMVIY73	N. A.	N. A.	Patented	[3]
PMID28117607-Compound-5	DMPBNFM	N. A.	N. A.	Patented	[3]
PMID28117607-Compound-6	DM68B1R	N. A.	N. A.	Patented	[3]
PMID28117607-Compound-7	DMJZREU	N. A.	N. A.	Patented	[3]
Pyridopyrimidinone derivative 1	DMZ6TSD	N. A.	N. A.	Patented	[3]
Pyridopyrimidinone derivative 2	DMUF63N	N. A.	N. A.	Patented	[3]
Pyridopyrimidinone derivative 3	DMHSDUR	N. A.	N. A.	Patented	[3]
Pyrrolo-pyridazine derivative 1	DMQ2U54	N. A.	N. A.	Patented	[3]
Pyrrolo-pyridine derivative 1	DM9K5CI	N. A.	N. A.	Patented	[3]
Pyrrolo-pyridine derivative 2	DMVNY5I	N. A.	N. A.	Patented	[3]
Pyrrolo-pyrimidine derivative 1	DMEVXT0	N. A.	N. A.	Patented	[3]
Pyrrolo-pyrimidine derivative 10	DMR0ZU6	N. A.	N. A.	Patented	[3]
Pyrrolo-pyrimidine derivative 11	DMEIDC0	N. A.	N. A.	Patented	[3]
Pyrrolo-pyrimidine derivative 8	DMZH27I	N. A.	N. A.	Patented	[3]
Pyrrolo-pyrimidine derivative 9	DMJEV86	N. A.	N. A.	Patented	[3]

6 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GNE-7915	DMYWM56	Discovery agent	N.A.	Investigative	[4]
GNE-9605	DMLXR90	Discovery agent	N.A.	Investigative	[4]
HMS3229G13	DMUPS48	Discovery agent	N.A.	Investigative	[5]
PF-06447475	DMEUT0W	Discovery agent	N.A.	Investigative	[6]
PF-06454589	DMWIVM3	Discovery agent	N.A.	Investigative	[6]
URMC-099	DMCJXWK	Discovery agent	N.A.	Investigative	[7]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Clinical pipeline report, company report or official report of Ionis
• [3] Leucine-rich repeat kinase 2 inhibitors: a patent review (2014-2016).Expert Opin Ther Pat. 2017 Jun;27(6):667-676.
• [4] Discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem. 2014 Feb 13;57(3):921-36.
• [5] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2059).
• [6] Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. J Med Chem. 2015 Jan 8;58(1):419-32.
• [7] Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J Med Chem. 2013 Oct 24;56(20):8032-48.